Clinical phenotypes and Genetic Mutations in Common Variable Immunodeficiency Amy Dowden, MD University of Iowa Hospitals ...
Patient 1 <ul><li>34 year old F  </li></ul><ul><li>PMH </li></ul><ul><ul><li>Hypothyroidism </li></ul></ul><ul><ul><li>Vit...
Laboratory/radiographic data <ul><li>Review from 1996 </li></ul><ul><ul><li>IgA 11 mg/dl (68-378) </li></ul></ul><ul><ul><...
CVID – the basics <ul><li>Diagnosis based on </li></ul><ul><ul><li>Quantitative immunoglobulin (Ig) levels and function </...
Other immune abnormalities <ul><li>Found in certain subsets of patients </li></ul><ul><ul><li>Defects in B cell survival/a...
CVID <ul><li>Significance </li></ul><ul><ul><li>1 in 25,000 (Europe/N. America) </li></ul></ul><ul><ul><li>Most common pri...
CVID – a heterogenous disease <ul><li>Most cases sporadic </li></ul><ul><li>10% - 15% familial </li></ul><ul><li>To date 4...
Patient 2 <ul><li>14 year old F  </li></ul><ul><li>PMH </li></ul><ul><ul><li>Chronic cough </li></ul></ul><ul><ul><li>Pneu...
Laboratory/radiographic data <ul><li>Quantitative Immunoglobulins </li></ul><ul><ul><li>IgA <5 mg/dl (68-378) </li></ul></...
Laboratory/radiographic data <ul><li>Normal sweat chloride test </li></ul><ul><li>Normal ciliary ultrastructure </li></ul>...
Laboratory/radiographic data <ul><li>Functional antibody deficiency </li></ul><ul><li>In vitro studies </li></ul><ul><ul><...
Patient 3 <ul><li>12 year old M  </li></ul><ul><li>PMH </li></ul><ul><ul><li>Upper respiratory tract infections </li></ul>...
Patient 4 <ul><li>17 year old F  </li></ul><ul><li>PMH </li></ul><ul><ul><li>Recurrent infections during infancy including...
Family tree ? CVID Unaffected ?
Research plan <ul><li>Establishment of a clinical phenotype database </li></ul><ul><li>Identify molecular basis for unknow...
Research Background <ul><li>At UIHC we follow 70+ patients with CVID </li></ul><ul><ul><li>4 family clusters </li></ul></u...
Specific Aims <ul><li>Develop distinct clinical phenotypes </li></ul><ul><li>Determine specific mutations using gene chip ...
Inclusion/exclusion criteria <ul><li>Inclusion  </li></ul><ul><ul><li>Individuals meeting the criteria for CVID </li></ul>...
Why identify molecular defects <ul><li>Provide a definitive diagnosis </li></ul><ul><li>Establish a diagnosis in atypical ...
Benefits of molecular diagnosis <ul><li>Costs progressively decreasing </li></ul><ul><li>Short turn around time </li></ul>...
 
 
Overview <ul><li>Cases </li></ul><ul><li>Background information on CVID </li></ul><ul><li>Review known genetic mutations <...
Impaired ability to produce specific antibodies   Draw date    Pre  8-7-06  Post  9-7-06  Fold-increase   Pneumovax type 1...
IgA Deficiency (IgAD) <ul><li>Most common primary immune deficiency  </li></ul><ul><li>Absent or low levels of IgA (<7 mg/...
Families with IgAD and CVID <ul><li>Genetic linkage analysis </li></ul><ul><ul><li>Susceptibility loci within the MHC locu...
Failure to produce antibodies <ul><li>Due to failure of B cells to differentiate into a sufficient number of plasma cells ...
ICOS (Inducible costimulatory receptor) <ul><li>Immunoglobulin-like costimulatory molecule </li></ul><ul><li>Member of CD2...
ICOS <ul><li>Involved in cytokine secretion </li></ul><ul><ul><li>Interleukin (IL)-4, IL-5, IL-6, IL-10, tumor necrosis fa...
ICOS <ul><li>Grimbacher  et al.  2003 </li></ul><ul><li>Individuals with </li></ul><ul><ul><li>Decreased IgG, M, A </li></...
TACI (TNF receptor family member transmembrane activator and calcium-modulator and cyclophilin ligand interactor) <ul><li>...
TACI <ul><li>Expressed on peripheral B cells </li></ul><ul><ul><li>Preferentially late transitional and marginal zone B ce...
TACI – mutation in CVID <ul><li>Autosomal dominant </li></ul><ul><li>Autosomal recessive </li></ul><ul><li>6 mutations ide...
TACI <ul><li>No distince B cell phenotype </li></ul><ul><li>Lymphoproliferative diseases and auto-immune disorders </li></...
CD19 <ul><li>Member of the B cell antigen receptor  (BCR) complex </li></ul><ul><li>BCR lowers the threshold for activatio...
CD19 <ul><li>Only 4 patients </li></ul><ul><ul><li>Undetectable (1) </li></ul></ul><ul><ul><li>Barely detectable </li></ul...
BAFF-R <ul><li>Only 1 individual identified </li></ul><ul><ul><li>Mutation also present in an unaffected relative </li></u...
Patient 1 <ul><li>TNFRSF13B sequencing </li></ul><ul><ul><li>Unlikely to be associated with CVID </li></ul></ul><ul><ul><l...
Draw date  Pre  2-25-08 Post  3-24-08 Fold-increase Diphtheria 0.03 U/mL 0.14 U/mL 4.7 Tetanus 0.43 IU/mL 1.13 IU/mL 2.6 D...
Patient 3 <ul><li>Quantitative Immunoglobulins </li></ul><ul><ul><li>IgA 52 mg/dl (68-378) </li></ul></ul><ul><ul><li>IgG ...
Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, Fieschi C, Thon V, Abedi MR, Hammarstrom L.  Common Varia...
Manifestations of CVID <ul><li>Recurrent upper and lower respiratory tract infections </li></ul><ul><ul><li>Encapsulated a...
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Amy Dowden, MD

  1. 1. Clinical phenotypes and Genetic Mutations in Common Variable Immunodeficiency Amy Dowden, MD University of Iowa Hospitals and Clinics Clinical Immunology Society School in Hypersensitivity and Allergic Diseases August 23, 2008
  2. 2. Patient 1 <ul><li>34 year old F </li></ul><ul><li>PMH </li></ul><ul><ul><li>Hypothyroidism </li></ul></ul><ul><ul><li>Vitiligo </li></ul></ul><ul><ul><li>Pernicious anemia </li></ul></ul><ul><ul><li>Bronchiectasis </li></ul></ul><ul><ul><li>Recurrent pneumonias </li></ul></ul><ul><ul><li>IgA deficiency </li></ul></ul><ul><li>FH </li></ul><ul><ul><li>2 healthy siblings </li></ul></ul><ul><ul><li>3 children adopted out, 1 with oophorectomy due to cancer at age 2 </li></ul></ul><ul><li>PE </li></ul><ul><ul><li>Cachetic, temporal wasting </li></ul></ul><ul><ul><li>Vitiligo </li></ul></ul><ul><ul><li>Bilateral rhonchi </li></ul></ul>
  3. 3. Laboratory/radiographic data <ul><li>Review from 1996 </li></ul><ul><ul><li>IgA 11 mg/dl (68-378) </li></ul></ul><ul><ul><li>IgG 965 mg/dl (694-1618) </li></ul></ul><ul><ul><li>IgM 71 mg/dl (60-263) </li></ul></ul><ul><ul><li>In vitro studies </li></ul></ul><ul><ul><ul><li>Decreased response to recall antigens </li></ul></ul></ul><ul><ul><li>Functional antibody deficiency </li></ul></ul><ul><ul><li>Sinusitis on CT </li></ul></ul><ul><li>Lost to follow up </li></ul><ul><li>Current </li></ul><ul><ul><li>IgA 19 mg/dl (68-378) </li></ul></ul><ul><ul><li>IgG 308 mg/dl (694-1618) </li></ul></ul><ul><ul><li>IgM 45 mg/dl (60-263) </li></ul></ul><ul><ul><li>Functional antibody deficiency </li></ul></ul>
  4. 4. CVID – the basics <ul><li>Diagnosis based on </li></ul><ul><ul><li>Quantitative immunoglobulin (Ig) levels and function </li></ul></ul><ul><li>Quantitative IgG < 2 standard deviations below mean </li></ul><ul><li>May have decreased IgA and IgM </li></ul><ul><li>Impaired ability to produce specific antibodies on vaccination </li></ul><ul><li>Exclusion of other causes for antibody deficiency </li></ul>
  5. 5. Other immune abnormalities <ul><li>Found in certain subsets of patients </li></ul><ul><ul><li>Defects in B cell survival/activation </li></ul></ul><ul><ul><li>Decreased circulating memory B cells </li></ul></ul><ul><ul><li>T-cell signaling defects </li></ul></ul><ul><ul><li>Abnormal cytokine secretion </li></ul></ul>Castigli E, Geha RS. Molecular basis of Common Variable Immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740-6.
  6. 6. CVID <ul><li>Significance </li></ul><ul><ul><li>1 in 25,000 (Europe/N. America) </li></ul></ul><ul><ul><li>Most common primary immune disorder requiring treatment </li></ul></ul><ul><ul><li>Significant morbidity/mortality </li></ul></ul><ul><li>Manifestations </li></ul><ul><ul><li>Recurrent upper and lower respiratory tract infections </li></ul></ul><ul><ul><ul><li>Encapsulated and atypical bacteria </li></ul></ul></ul><ul><ul><li>Autoimmune disorders (~20%) </li></ul></ul><ul><ul><li>Lymphoproliferation/ splenomegaly (1/3) </li></ul></ul>
  7. 7. CVID – a heterogenous disease <ul><li>Most cases sporadic </li></ul><ul><li>10% - 15% familial </li></ul><ul><li>To date 4 known mutations </li></ul><ul><ul><li>ICOS </li></ul></ul><ul><ul><li>TACI </li></ul></ul><ul><ul><li>CD19 </li></ul></ul><ul><ul><li>BAFF-R </li></ul></ul><ul><li>Misdiagnosis </li></ul><ul><ul><li>(Bruton’s) X-linked agammaglobulinemia </li></ul></ul><ul><ul><li>X-linked lymphoproliferative disorder (SH2DIA) </li></ul></ul><ul><ul><li>X-linked Hyper IgM (CD40L) </li></ul></ul>
  8. 8. Patient 2 <ul><li>14 year old F </li></ul><ul><li>PMH </li></ul><ul><ul><li>Chronic cough </li></ul></ul><ul><ul><li>Pneumonia (times 2) </li></ul></ul><ul><ul><li>Recurrent otitis media </li></ul></ul><ul><ul><li>Few warts </li></ul></ul><ul><ul><li>Sertoli-Leydig tumor at age 2 </li></ul></ul><ul><li>FH </li></ul><ul><ul><li>2 healthy siblings </li></ul></ul><ul><ul><li>adopted </li></ul></ul><ul><li>PE </li></ul><ul><ul><li>Small cervical LAD </li></ul></ul><ul><ul><li>Bilateral tympanostomy tubes </li></ul></ul><ul><ul><li>Few warts on hands </li></ul></ul><ul><ul><li>Course breath sounds </li></ul></ul>
  9. 9. Laboratory/radiographic data <ul><li>Quantitative Immunoglobulins </li></ul><ul><ul><li>IgA <5 mg/dl (68-378) </li></ul></ul><ul><ul><li>IgG 535 mg/dl (694-1618) </li></ul></ul><ul><ul><li>IgM 52 mg/dl (60-263) </li></ul></ul><ul><li>Normal liver, kidney and thyroid function </li></ul><ul><li>Sinusitis on sinus CT </li></ul>
  10. 10. Laboratory/radiographic data <ul><li>Normal sweat chloride test </li></ul><ul><li>Normal ciliary ultrastructure </li></ul><ul><li>Immunophenotyping </li></ul><ul><ul><li>↓ CD19 B lymphocytes 55/MM3 (122-690) </li></ul></ul><ul><li>Chest x-ray </li></ul><ul><ul><li>Right lower lobe infiltrate </li></ul></ul>
  11. 11. Laboratory/radiographic data <ul><li>Functional antibody deficiency </li></ul><ul><li>In vitro studies </li></ul><ul><ul><li>Normal fresh and IL-2 enhansed Natural Killer cell activity </li></ul></ul><ul><ul><li>↓ Lymphocytic response to alloantigen </li></ul></ul><ul><ul><li>Slightly ↓ lymphocytic response to IL2 </li></ul></ul>
  12. 12. Patient 3 <ul><li>12 year old M </li></ul><ul><li>PMH </li></ul><ul><ul><li>Upper respiratory tract infections </li></ul></ul><ul><ul><li>Recurrent otitis media </li></ul></ul><ul><ul><li>Few warts in the past </li></ul></ul><ul><li>FH </li></ul><ul><ul><li>1 healthy sister </li></ul></ul><ul><ul><li>1 sister with CVID </li></ul></ul><ul><ul><li>adopted </li></ul></ul><ul><li>PE </li></ul><ul><ul><li>Bilateral tympanostomy tubes </li></ul></ul><ul><li>Normal CBC with differential </li></ul><ul><li>Normal CH50 </li></ul><ul><li>Quantitative Immunoglobulins </li></ul><ul><ul><li>IgA 52 mg/dl (68-378) </li></ul></ul><ul><ul><li>IgG 825 mg/dl (694-1618) </li></ul></ul><ul><ul><li>IgM 48 mg/dl (60-263) </li></ul></ul><ul><li>Functional antibody deficiency </li></ul>
  13. 13. Patient 4 <ul><li>17 year old F </li></ul><ul><li>PMH </li></ul><ul><ul><li>Recurrent infections during infancy including pneumonia and otitis </li></ul></ul><ul><ul><li>Dental caries </li></ul></ul><ul><ul><li>Few warts in the past </li></ul></ul><ul><li>FH </li></ul><ul><ul><li>1 brother with recurrent infections </li></ul></ul><ul><ul><li>1 sister with CVID </li></ul></ul><ul><ul><li>adopted </li></ul></ul><ul><li>Normal physical exam </li></ul><ul><li>Labs </li></ul><ul><ul><li>Normal quantitative immunoglobulin levels </li></ul></ul>
  14. 14. Family tree ? CVID Unaffected ?
  15. 15. Research plan <ul><li>Establishment of a clinical phenotype database </li></ul><ul><li>Identify molecular basis for unknown cases of CVID </li></ul><ul><ul><li>Known genetic defects account for 10-15% of cases of CVID </li></ul></ul><ul><ul><li>Focus on familial clusters </li></ul></ul><ul><ul><li>Similar phenotypes </li></ul></ul>
  16. 16. Research Background <ul><li>At UIHC we follow 70+ patients with CVID </li></ul><ul><ul><li>4 family clusters </li></ul></ul><ul><li>In the process of establishing a phenotype database for CVID </li></ul><ul><ul><li>Demographics, autoimmunity, cancer, gastrointestinal disease, infections, sinus disease, lymphoproliferative disease, family history, treatment, labs </li></ul></ul>
  17. 17. Specific Aims <ul><li>Develop distinct clinical phenotypes </li></ul><ul><li>Determine specific mutations using gene chip analysis from RNA obtained from CVID patients </li></ul><ul><li>Examine the serum cytokine profile in this population </li></ul>
  18. 18. Inclusion/exclusion criteria <ul><li>Inclusion </li></ul><ul><ul><li>Individuals meeting the criteria for CVID </li></ul></ul><ul><li>Exclusion </li></ul><ul><ul><li>Immunodeficiency of secondary causes </li></ul></ul><ul><ul><li>Individuals with known mutations </li></ul></ul>
  19. 19. Why identify molecular defects <ul><li>Provide a definitive diagnosis </li></ul><ul><li>Establish a diagnosis in atypical presentations </li></ul><ul><li>Permit prenatal diagnosis/genetic counseling </li></ul><ul><li>Prognostic/therapeutic implications </li></ul><ul><ul><li>Genotype-phenotype correlation </li></ul></ul><ul><ul><li>Early identification of affected presymptomatic individuals </li></ul></ul>
  20. 20. Benefits of molecular diagnosis <ul><li>Costs progressively decreasing </li></ul><ul><li>Short turn around time </li></ul><ul><li>High reproducibility </li></ul><ul><li>Patients don’t need to come back </li></ul><ul><li>Easy to trace individuality </li></ul><ul><li>DNA is easy to store and hard to destroy </li></ul>
  21. 23. Overview <ul><li>Cases </li></ul><ul><li>Background information on CVID </li></ul><ul><li>Review known genetic mutations </li></ul><ul><li>Research plan </li></ul>
  22. 24. Impaired ability to produce specific antibodies Draw date Pre 8-7-06 Post 9-7-06 Fold-increase Pneumovax type 1 0.65 Ug/ml 0.48 Ug/ml <1.0 Pneumovax type 3 0.02 Ug/ml 0.02 Ug/ml 1.0 Pneumovax type 4 0.04 Ug/ml 0.03 Ug/ml <1.0 Pneumovax type 5 0.22 Ug/ml 0.15 Ug/ml <1.0 Pneumovax type 6B 0.09 Ug/ml 0.07 Ug/ml <1.0 Pneumovax type 7F 0.02 Ug/ml 0.02 Ug/ml 1.0 Pneumovax type 8 0.05 Ug/ml 0.03 Ug/ml <1.0 Pneumovax type 9N 0.02 Ug/ml 0.01 Ug/ml <1.0 Pneumovax type 9V 0.08 Ug/ml 0.05 Ug/ml <1.0 Pneumovax type 12 0.03 Ug/ml 0.03 Ug/ml 1.0 Pneumovax type 14 6.78 Ug/ml 5.06 Ug/ml <1.0 Pneumovax type 18C 0.03 Ug/ml 0.02 Ug/ml <1.0 Pneumovax type 19F 0.44 Ug/ml 0.33 Ug/ml <1.0 Pneumovax type 23F 0.04 Ug/ml 0.03 Ug/ml <1.0
  23. 25. IgA Deficiency (IgAD) <ul><li>Most common primary immune deficiency </li></ul><ul><li>Absent or low levels of IgA (<7 mg/dL) </li></ul><ul><li>Subset of IgAD patients predisposed to recurrent infections (GI/sinopulmonary) </li></ul><ul><ul><li>Functional antibody deficiency </li></ul></ul><ul><li>IgAD may develop into CVID </li></ul><ul><li>IgAD and CVID may coexist in the same family </li></ul>
  24. 26. Families with IgAD and CVID <ul><li>Genetic linkage analysis </li></ul><ul><ul><li>Susceptibility loci within the MHC locus of chromosome 6 </li></ul></ul><ul><li>MHC class II genes play role in in antigen presentation to T H cells which provide help to B cells for proficient antibody production </li></ul><ul><li>IgAD and CVID may represent a range in the penetrance of the same disease </li></ul>Castigli E, Geha RS. Molecular basis of Common Variable Immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740-6 . Answers.com
  25. 27. Failure to produce antibodies <ul><li>Due to failure of B cells to differentiate into a sufficient number of plasma cells </li></ul><ul><li>IgAD </li></ul><ul><ul><li>Some patients have impaired switching to IgA others have a postswitch defect </li></ul></ul><ul><li>CVID </li></ul><ul><ul><li>Impaired somatic hypermutation </li></ul></ul><ul><ul><li>Evidence for a global isotype switching defect </li></ul></ul>
  26. 28. ICOS (Inducible costimulatory receptor) <ul><li>Immunoglobulin-like costimulatory molecule </li></ul><ul><li>Member of CD28 family </li></ul><ul><li>Expressed on activated T cells </li></ul><ul><li>Binds to ICOS-L expressed on APCs. </li></ul>
  27. 29. ICOS <ul><li>Involved in cytokine secretion </li></ul><ul><ul><li>Interleukin (IL)-4, IL-5, IL-6, IL-10, tumor necrosis factor (TNF)- α , interferon (IFN)- γ , and granulocyte-macrophage colony-stimulating factor (GM-CSF) </li></ul></ul><ul><li>Superinduction of IL-10 leads to terminal differentiation of B cells to plasma and memory cells </li></ul>
  28. 30. ICOS <ul><li>Grimbacher et al. 2003 </li></ul><ul><li>Individuals with </li></ul><ul><ul><li>Decreased IgG, M, A </li></ul></ul><ul><ul><li>Reduced B cells </li></ul></ul><ul><ul><li>Decreased CD27 + IgM - IgD - switched memory B cells </li></ul></ul><ul><ul><li>Decrease naïve CD27 - IgM + IgD + </li></ul></ul><ul><li>Impaired IL-10 and IL-17 secretion </li></ul><ul><li>Normal phenotype and function of CD4 + </li></ul><ul><li>All described individuals carry the same homozygous deletion. </li></ul><ul><li>Incidence 5% </li></ul>
  29. 31. TACI (TNF receptor family member transmembrane activator and calcium-modulator and cyclophilin ligand interactor) <ul><li>Two different cohorts </li></ul><ul><ul><li>CVID </li></ul></ul><ul><ul><li>IgA deficiency </li></ul></ul><ul><li>Same mutation within a pedigree in different individuals suggests phenotypes are variants of the same gene defect </li></ul>
  30. 32. TACI <ul><li>Expressed on peripheral B cells </li></ul><ul><ul><li>Preferentially late transitional and marginal zone B cells </li></ul></ul><ul><li>Interacts with BAFF and April </li></ul><ul><ul><li>BAFF (B cell activation factor of the TNF family receptor) </li></ul></ul><ul><ul><li>April is a proliferation-inducing ligand </li></ul></ul><ul><li>Following ligand binding the intracellular domain binds TRAFS (TNF-associated factors) leading to transcription factor upregulation </li></ul>Castigli E, Geha RS. Molecular basis of Common Variable Immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740-6 .
  31. 33. TACI – mutation in CVID <ul><li>Autosomal dominant </li></ul><ul><li>Autosomal recessive </li></ul><ul><li>6 mutations identified to date </li></ul><ul><ul><li>3 missense </li></ul></ul><ul><ul><li>2 nonsense </li></ul></ul><ul><ul><li>1 base insertion </li></ul></ul><ul><li>8-10% of patients with CVID </li></ul>Castigli E, Geha RS. TACI, isotype switching, CVID and IgAD. Immunol Res. 2007;38(1-3):102-11.
  32. 34. TACI <ul><li>No distince B cell phenotype </li></ul><ul><li>Lymphoproliferative diseases and auto-immune disorders </li></ul>Figure adapted from Castigli E, Geha RS. Molecular basis of Common Variable Immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740-6.
  33. 35. CD19 <ul><li>Member of the B cell antigen receptor (BCR) complex </li></ul><ul><li>BCR lowers the threshold for activation after antigen engagement </li></ul><ul><li>Link between innate and adaptive immune systems </li></ul>
  34. 36. CD19 <ul><li>Only 4 patients </li></ul><ul><ul><li>Undetectable (1) </li></ul></ul><ul><ul><li>Barely detectable </li></ul></ul><ul><li>Normal B cells in bone marrow and periphery </li></ul><ul><li>Decreased CD5 + B cells and CD27 + memory B cells </li></ul><ul><li>Normal B cell development but poor response to antigenic stimuli and inability to mount humoral response </li></ul><ul><li>No autoimmune features or lympho-proliferation (unlike TACI) </li></ul>
  35. 37. BAFF-R <ul><li>Only 1 individual identified </li></ul><ul><ul><li>Mutation also present in an unaffected relative </li></ul></ul><ul><li>Limited information at present </li></ul><ul><li>Individual lacks BAFF-R on B cells </li></ul><ul><li>Phenotyping reveals a block at the transitional B cell stage </li></ul>Castigli E, Geha RS. Molecular basis of Common Variable Immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740-6.
  36. 38. Patient 1 <ul><li>TNFRSF13B sequencing </li></ul><ul><ul><li>Unlikely to be associated with CVID </li></ul></ul><ul><ul><li>Correlagen </li></ul></ul><ul><ul><li>Gene product is TACI </li></ul></ul>
  37. 39. Draw date Pre 2-25-08 Post 3-24-08 Fold-increase Diphtheria 0.03 U/mL 0.14 U/mL 4.7 Tetanus 0.43 IU/mL 1.13 IU/mL 2.6 Draw date: Pneumovax type 1 0.01 Ug/ml 0.06 Ug/ml NP Pneumovax type 3 0.58 Ug/ml 2.07 Ug/ml 3.6 Pneumovax type 4 0.01 Ug/ml 0.15 Ug/ml NP Pneumovax type 5 0.05 Ug/ml 0.03 Ug/ml NP Pneumovax type 6B 0.02 Ug/ml 0.06 Ug/ml NP Pneumovax type 7F 0.03 Ug/ml 0.11 Ug/ml NP Pneumovax type 8 0.05 Ug/ml 0.59 Ug/ml NP Pneumovax type 9N 0.01 Ug/ml 0.03 Ug/ml NP Pneumovax type 9V 0.03 Ug/ml 0.12 Ug/ml NP Pneumovax type 12F 0.04 Ug/ml 0.05 Ug/ml NP Pneumovax type 14 0.01 Ug/ml 0.02 Ug/ml NP Pneumovax type 18C 0.01 Ug/ml 0.02 Ug/ml NP Pneumovax type 19F 0.07 Ug/ml 0.10 Ug/ml NP Pneumovax type 23 0.01 Ug/ml 0.02 Ug/ml NP
  38. 40. Patient 3 <ul><li>Quantitative Immunoglobulins </li></ul><ul><ul><li>IgA 52 mg/dl (68-378) </li></ul></ul><ul><ul><li>IgG 825 mg/dl (694-1618) </li></ul></ul><ul><ul><li>IgM 48 mg/dl (60-263) </li></ul></ul><ul><li>Normal CBC with differential </li></ul><ul><li>Normal CH50 </li></ul><ul><li>Functional antibody deficiency </li></ul>
  39. 41. Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, Fieschi C, Thon V, Abedi MR, Hammarstrom L. Common Variable Immunodeficiency Disorders: Division into distinct clinical phenotypes. Blood. 2008 Mar;112:277-86.
  40. 42. Manifestations of CVID <ul><li>Recurrent upper and lower respiratory tract infections </li></ul><ul><ul><li>Encapsulated and atypical bacteria </li></ul></ul><ul><li>Autoimmune disorders (~20%) </li></ul><ul><li>Lymphoproliferation/ splenomegaly (1/3) </li></ul>
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