Common Variable Immunodeficiency

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Common Variable Immunodeficiency

  1. 1. Morning Conference July 22, 2009 Araya Tangwitoon, MD
  2. 2. History • A 14-year-old girl presented with chronic rhinosinusitis and recurrent otitis media. • She had a history of recurrent otitis media since 8-yr-old & a history of recurrent rhinosinusitis since 10-yr-old, which not responded to treatment with various antibiotics.
  3. 3. • Nasal discharge culture (1st): P. aeruginosa Sensitivity to ciprofloxacin • Nasal discharge culture (2nd): M. morganii Sensitivity to amikacin, ceftazidime, cefoxitin, imipenem • CBC: Hb 12.8 mg/dL Hct 39.2% WBC 8100 /mm3 N 67% L 26% M 4% Eo1.4% Plt 216,000 /mm3 • Serum IgG 12.4 mg/dL (600-1600) IgM <18.6 mg/dL (40-160) IgA <5.91 mg/dL (80-480)
  4. 4. Problem Lists • A 14-yr-old girl with CRS • Recurrent sinopulmonary tract infections • Panhypogammaglobulinemia • Secondary hypogammaglobulinemia • Primary Immunodeficiency
  5. 5. Physical Examination • A Thai girl, good consciousness, well co-operate • BW 48 kg (P50-75), Ht 158 cm (P50-75) • HEENT: not pale, no jaundice Rt ear: TM perforation with opacity & mucoid discharge Nose: purulent discharge both nostrils, Inferior turbinate 3+ both Tonsils: 1+, mucopurulent postnasal drip • Heart: normal S1S2, no murmur • Lungs: Clear, Rt = Lt • Abd: soft, not tender, spleen: just palpable, no hepatomegaly • Ext: normal
  6. 6. • Flow cytometry: WBC 9,050/ul Absolute total lymphocyte 2,054/ul Lymphocyte 22.7% %CD3 92% Absolute CD3 1,890 /ul %CD4 55% Absolute CD4 1,130 /ul %CD8 34% Absolute CD8 698 /ul %CD19 2% %CD56 6%
  7. 7. • Serum IgG < 7.3 mg/dL (600-1600) IgM < 18.6 mg/dL (40-160) IgA < 5.91 mg/dL (80-480) • Flow cytometry: WBC 6,150 /ul ALC 1,550/ul Lymphocyte 25.2% %CD3 91% Absolute CD3 1,411 /ul %CD4 54% Absolute CD4 837 /ul %CD8 34% Absolute CD8 527 /ul %CD19 1% %CD56 5%
  8. 8. Problem Lists • A 14-yr-old girl with CRS • Recurrent sinopulmonary tract infections • Panhypogammaglobulinemia • Low number of circulating B cell • Secondary hypogammaglobulinemia • Primary Immunodeficiency – Autosomal Agammaglobulinemia – X-Linked Agammaglobulinemia – Common Variable Immunodeficiency
  9. 9. Secondary hypogammaglobulinemia • Drug-induced • Excessive loss of immunoglobulins – Anticonvulsants – Protein-losing enteropathy (e.g., carpamazepine – Nephrotic range proteinuria and phenytoin) – Severe burns – Gold salts – Penicillamine • Malignancy – Antimalarial agents – Chronic lymphocytic leukemia – Methotrexate – Non-Hodgkin's B-cell lymphoma • Infectious diseases – Epstein-Barr virus
  10. 10. XLA or AR CVID Agammaglobulinemia Age at onset XLA: 6-12 months Any ages; peak in first & third AR: younger than XLA decades Sex XLA: males males and females AR: males and females Clinical recurrent infections; recurrent infections, manifestations more severe in AR autoimmune manifestations, agammaglobulinemia lymphoma & other selected cancers. Lymphoid tissue hypoplasia or absent Normal-sized or Enlarged Serum Ig level profound hypogammaglobulinemia Decreased IgG, IgA (IgG, IgA and IgM) and/or IgM Peipheral B Cells almost complete absence of normal or low number peripheral B cells, as defined by CD19 & CD20 expression (<2%) Molecular analysis XLA; BTK mutation ICOS, CD19, TACI, BAFF-R, Msh5 AR; μ heavy chain, Igα, Igß, λ5/VpreB, BLNK
  11. 11. AR Agammaglobulinemia XLA CVID Berek C et al. Clinical Immunology Principles and Practice.3rd Edition.
  12. 12. Autosomal Recessive Agammaglobulinemia • When compared with XLA – an earlier onset of disease – more severe complications • Females with early onset infections, profound hypogammaglobulinemia and absent B cells • Male patients with negative BTK mutation analysis results Schroeder HW Jr. Clinical Immunology Principles and Practice.3rd Edition. Aghamohammadi A et al. Primary Immunodeficiency Diseases: Definition, Diagnosis, and Management 1st edition.
  13. 13. • 4 pts: homozygous mutation in IGHM • 2 pts: compound heterozygous variations in VpreB1 gene • Several new single nucleotide polymorphisms both in the μHC and in the λ5- like/VpreB-coding genes were identified. S Ferrari et al. Genes and Immunity 2007;8:325–33.
  14. 14. Clinical findings in AR agammaglobulinemia Lopez-Granados E, Porpiglia A, Hogan MB, et al. J Clin Invest 2002; 110:1029-35.
  15. 15. • A 10-month-old Japanese girl with frequent respiratory infections and otitis media (onset of infections: 8-month-old) • Her father was diagnosed as having XLA. • Her serum IgG 6 mg/dL, IgA 1 mg/dL, IgM 5 mg/dL • Flow cytometric analysis – the lack of peripheral B cells with the block of B-cell differentiation in the stages between pro-B cells and pre-B cells in the bone marrow – the defect of the Bruton tyrosine kinase (BTK) expression on monocytes Takada H et al. Blood. 2004;103:185-187.
  16. 16. Defect of BTK and block of B-cell differentiation. Patient Healthy control Patient Healthy control Paternal Grand mom Pt Mother Brother Father Takada H et al. Blood. 2004;103:185-187
  17. 17. • Maternally derived X chromosome was exclusively inactivated in peripheral blood & oral mucosal cells. XLA (Heterozygous abnormality of the BTK gene & nonrandom X inactivation of maternally derived X chromosome in which normal BTK gene is located.) Takada H et al. Blood 2004;103:185-187.
  18. 18. Problem Lists • A 14-yr-old girl with CRS • Recurrent sinopulmonary tract infections • Panhypogammaglobulinemia • Low number of circulating B cell • Secondary hypogammaglobulinemia • Primary Immunodeficiency – Autosomal Agammaglobulinemia – X-Linked Agammaglobulinemia – Common Variable Immunodeficiency
  19. 19. Physical Examination • A Thai girl, good consciousness, well co-operate • BW 48 kg (P50-75), Ht 158 cm (P50-75) • HEENT: not pale, no jaundice Rt ear: TM perforation with opacity & mucoid discharge Nose: purulent discharge both nostrils, Inferior turbinate 3+ both Tonsils: 1+, mucopurulent postnasal drip • Heart: normal S1S2, no murmur • Lungs: Clear, Rt = Lt • Abd: soft, not tender, spleen: just palpable, no hepatomegaly • Ext: normal
  20. 20. Common Variable Immunodeficiency
  21. 21. CVID • The most common symptomatic PID • A group of genetically, immunologically & clinically heterogeneous disorders • Hypogammaglobulinemia & recurrent infections • Complicated by autoimmunity, granulomatous inflammation, lymphoproliferation & malignancy • Inherited in 10-20% of patients • Associated genetic defects: ICOS, TACI, CD19, BAFF-R and Msh-5
  22. 22. CVID: Definition • Hypogammaglobulinaemia of > 2 immunoglobulin isotypes (significant reduction of IgG (>2SD), reduction of IgA or IgM) • Recurrent infections • Impaired functional antibody responses • Exclusion of other primary antibody deficiency syndromes & secondary causes of hypogammaglobulinemia www.ESID.org
  23. 23. Clinical Features of CVID patients
  24. 24. CVID: Age at onset & diagnosis No. of Delay Age at Age at Age at CVID Diagnosis; evaluation; year onset; year Diagnosis; year patients year Chapel H et al. 334 mean±SD: Mean: 26.3 Mean: 33.5 NA Blood 2008;112: 49.4±16.3 median: 24 median: 33 277-86. (11-90) Wehr C et al. 303 mean±SD: mean±SD: mean±SD: NA Blood 2008;111:77-85. 47±17 27±17 35±16 (10-84) Oksenhendler E et al. 252 Median: 44 Median: 19 Median: 33.9 Median: 6.9 Clinical Infectious (12-87) (0-55) Diseases2008;46:1547–54 URSCHEL S et al. 32 < 18 NA Median: Median: J Pediatr 2009;154: 10.4±4.3 5.8±4.2 888-94. (1.1-17.4) (0.2-14.3) Llobet et al. 22 < 18 NA Median: 7.8 NA Pediatr Allergy Immunol (2.5-16) 2009: 20: 113–118.
  25. 25. Park MA et al. Lancet 2008;372:489-502.
  26. 26. Infectious complications in CVID patients Oksenhendler E et al. Clinical Infectious Diseases 2008;46:1547–54.
  27. 27. Chapel H and Cunningham-Rundles C. British Journal of Haematology 2009;145:709–727. (originally published in Blood. Chapel H. et al. Blood 2008;112:277–286.)
  28. 28. Chapel H et al. Blood 2008;112: 277-86.
  29. 29. only breakthrough a noninfectious complication (with or without breakthrough infections). infections Lymphocytic infiltration: n=38 Autoimmunity: n=72 Enteropathy: n=7 Malignancy: n=1 lymphocytic infiltration+autoimmunity: n=28 Enteropathy+lymphocytic infiltration: n=8 lymphocytic infiltration+malignancy: n=1 Enteropathy+autoimmunity: n=3 Autoimmunity+malignancy: n=2 autoimmunity, lymphocytic infiltration, enteropathy, malignancy: n=1 Autoimmunity+lymphocytic infiltration+enteropathy: n=9 Autoimmunity+lymphocytic infiltration+malignancy: n=4 Lymphocytic infiltration+enteropathy+malignancy: n=1 Chapel H et al. Blood 2008;112: 277-86.
  30. 30. Disease complication prevalences WEHR et al. CHAPEL et al (Blood 2008; 111:77-85.) (Blood. 2008;112:277-86.) No. of CVID patients 303 334 Splenomegaly, % 40.5 30 Lymphadenopathy, % 26.2 15 Granulomatous disease, % 11.6 8 Autoimmune phenomena*, % 20.3 25 Autoimmune cytopenia, % 20.2 12 *not include autoimmune cytopenia
  31. 31. Wehr C et al. Blood 2008;111:77-85.
  32. 32. Chapel H et al. Blood 2008;112: 277-86.
  33. 33. URSCHEL S et al. J Pediatr 2009;154:888-94.
  34. 34. Immunological analysis of CVID patients
  35. 35. European cohort Serum Immunoglobulin at diagnosis Serum IgG < 1 g/L Serum IgG 1.1-3 g/L Serum IgG >3, <6.5 g/L United States Cohort Chapel H and Cunningham-Rundles C. British Journal of Haematology 2009;145:709–727.
  36. 36. Pediatric population diagnosed of CVID Serum level in each patient at first diagnosis IgG IgM IgA URSCHEL S et al. J Pediatr 2009;154:888-94.
  37. 37. Peripheral B Cells No significant associations with clinical phenotypes Chapel H et al. Blood 2008;112: 277-286.
  38. 38. Association of clinical phenomena with dysregulated B-cell subpopulations. Wehr C et al. Blood 2008;111:77-85.
  39. 39. Pediatric population diagnosed of CVID Llobet et al. Pediatr Allergy Immunol 2009: 20: 113–118.
  40. 40. URSCHEL S et al. J Pediatr 2009;154:888-94.
  41. 41. Classification systems for CVID
  42. 42. Peripheral blood B-cell subsets Park MA et al. Lancet 2008;372:489-502.
  43. 43. Classification systems for CVID Expert Review of Clinical Immunology 2009.
  44. 44. Evaluation of the Paris and Freiburg classification scheme. P < 0.001 P = 0.03 P = 0.04 P = 0.02 P = 0.02 Wehr C et al. Blood 2008;111:77-85.
  45. 45. P < 0.001 P = 0.002 P < 0.01 P = 0.009 P = 0.03 P < 0.001 P = 0.049 P = 0.016 Wehr C et al. Blood 2008;111:77-85.
  46. 46. Genetics of CVID
  47. 47. Genetics for CVID • ICOS • CD19 • TACI (TNFRSF13B) • BAFF-R (TNFRSF13C) • Msh5
  48. 48. The inducible costimulator (ICOS) gene • Germinal center formation • Memory B cell development • Provide T-cell dependent antibody response for B cell Park MA et al. Lancet 2008;372:489-502.
  49. 49. Fig. 1. Inducible co-stimulator molecule (ICOS) : ICOS-L signalling can results in multiple pathways. C. Bacchelli et al. Clinical and Experimental Immunology 2007;149: 401–9.
  50. 50. ICOS Deficiency • About 2% of patients with CVID • Inherited as autosomal recessive trait • 9 CVID patients from 4 apparently unrelated families descended from a common founder • Geographical location: along the river Danube • Serum IgG & IgA levels were markedly reduced in all patients – IgG < 1.9-2.55 g/L – IgA < 0.06-0.58 g/L • Serum IgM level – reduced in 6/9 patients – low normal values in 3/9 patients Yong et al. Immunological Reviews 2009;229: 101–113. Park MA et al. Lancet 2008;372:489-502. C. Bacchelli et al. Clinical and Experimental Immunology 2007, 149: 401–409.
  51. 51. • Circulating B cells – Markedly reduced in 5/9 patients – Slightly elevated in 2/9 patients • Switched memory B cells: absent in all patients • Few abnormalities in T-cell phenotype & function – 3 patients had an inverted CD4⁄CD8 ratio. – Normal in vitro proliferation responses when stimulated with mitogens & antigens • Marked impairment of germinal center formation • The clinical phenotype shows nearly all complication (autoimmunity, benign lymphoproliferation, chronic granulomatous inflammation & malignancy). Yong et al. Immunological Reviews 2009;229: 101–113. C. Bacchelli et al. Clinical and Experimental Immunology 2007;149: 401–409.
  52. 52. The B cell receptor signaling complex Park MA et al. Lancet 2008;372:489-502 Schaffer AA et al. Current Opinion in Genetics & Development 2007, 17:201–12.
  53. 53. CD19 Deficiency • 4 patients with homozygous mutations in the CD19 gene, from 2 unrelated families – increased susceptibility to infection – hypogammaglobulinemia – normal numbers of CD20+ B cells – expression of CD 19 on B cells • undetectable in 1/4 patients • barely detectable in 3/4 patients • Numbers of CD27+ memory B cells & CD5+ B cells • Normal germinal center formation • Poor antibody response to rabies vaccination • No autoimmune features or signs of lymphoproliferation van Zelm MC, Reisli I, van der Burg M et al. N Engl J Med 2006;354:1901-12.
  54. 54. van Zelm MC, Reisli I, van der Burg M et al. N Engl J Med 2006;354:1901-12.
  55. 55. The APRIL–BAFF network Park MA et al. Lancet 2008;372:489-502
  56. 56. Interactions of BAFF, APRIL with their receptors C. Bacchelli et al. Clinical and Experimental Immunology 2007;149: 401–9.
  57. 57. TACI Mutation • Prevalence: 10-20% of CVID patients • Risk factors, not solely disease-causing in CVID • Associated with – Lymphoproliferation • splenomegaly • tonsillar hyperplasia • follicular nodular hyperplasia of GI – Autoimmunity • hemolytic anaemia • autoimmune thrombocytopaenia • thyroiditis Park MA et al. Lancet 2008;372:489-502. Young PFK et al. Immunol Allergy Clin N Am 2008;28:367-86. C. Bacchelli et al. Clinical and Experimental Immunology 2007;149: 401–409.
  58. 58. TACI Mutation • A multicenter study involving 564 unrelated CVID patients • 8.8% (50/564) of the patients carried at least 1 mutated TACI allele. – 4% (2/50): homozygous mutations – 14% (7/50): compound heterozygous mutations – 82% (41/50): heterozygous mutations Salzer U et al. Blood 2009;113:1967-76.
  59. 59. • TACI C104R & A181E – mutational 'hotspots‘ – Approximately 80% of the sequence variants in TACI – present in a heterozygous state in 2% of 675 healthy controls Salzer U et al. Blood 2009;113:1967-76.
  60. 60. Salzer U et al. Blood 2009;113:1967-76.
  61. 61. Zhang et al. 2007 • 7.3% (13/176) of subjects had Heterozygous TACI mutations. • Autoimmune thrombocytopenia – 46% of subjects with mutations – 12% of subjects without mutations • Mutations in TACI significantly predispose to autoimmunity and lymphoid hyperplasia in CVID. • Splenomegaly and splenectomy were significantly increased (P 5 .012; P 5 .001). • 8 first-degree relatives from 5 families had the same mutations but were not immune-deficient. Zhang et al. J Allergy Clin Immunol 2007;120:1178-85
  62. 62. Zhang et al. J Allergy Clin Immunol 2007;120:1178-85.
  63. 63. Immunologic phenotype of TACI-deficient patients. Salzer U et al. Blood 2009;113:1967-76.
  64. 64. 36% (18/50) Autoimmunity & lymphoproliferation in TACI deficiency 60% (30/50) Salzer U et al. Blood 2009;113:1967-76.
  65. 65. BAFF-R Deficiency • Described in only 1 patient • a 60-year-old male with hypogammaglobulinaemia • Profound reduction of both class switch (CD27+, IgM-, IgD-) & non-switched memory (CD27+, IgM+, IgD+) • Transitional B cell (CD38+++, IgM++) • Plasmablasts (CD38+++, IgM-) Park MA et al. Lancet 2008;372:489-502. C. Bacchelli et al. Clinical and Experimental Immunology 2007;149: 401–409.
  66. 66. MutS 5 (Msh5) • A gene encoded in the central MHC class III region • A critical role in regulating meiotic homologous recombination • A role in class switch recombination • Msh5 Mutation: associated with CVID and selective IgA deficiency. Young PFK et al. Immunol Allergy Clin N Am 2008;28:367-86. Sekine et al. Proc Natl Acad Sci U S A. 2007 ;104(17):7193-8.
  67. 67. Gene Frequency (chromosomal Inheritance Phenotype B-cell phenotype Clinical phenotype (%) location) ICOS (2q33) 2 AR CVID Low numbers of Recurrent respiratory B-cell & memory B infections, cells autoimmunity, granulomata and malignancy TNFRSF13B/ 8-20 AD • CVID, No specific B-cell Recurrent respiratory TACI • IgG phenotype infections, increased (17p11.2) subclass rates of benign deficiency lymphoproliferation and • sIgAD increased rates of autoimmunity CD19 1 AR CVID Decrease in class Recurrent respiratory (16p11.2) switched memory B infections cells, low CD21 expression on B cells, normal numbers of CD20+ mature B cells in peripheral blood TNFRSF13C/ <1 AR CVID Low B-cell numbers, Recurrent respiratory BAFF-R relative increase in infections (22q13.1- transitional B cells q13.31) and low numbers of memory B cells Park MA et al. Lancet 2008;372:489-502. Expert Review of Clinical Immunology, March 2009, Vol. 5, No. 2, Pages 167-180
  68. 68. Therapeutic Management • Prevention of recurrent and chronic infections by Immunoglobulin therapy • Antibiotic therapy of breakthrough infections • Treatment of associated disease complications and sequelae
  69. 69. • A 14-yr-old girl with CRS • Recurrent sinopulmonary tract infections • Panhypogammaglobulinemia • Low number of circulating B cell • Splenomegaly Common Variable Immunodeficiency
  70. 70. Management • Treatment of infections • Intravenous immunoglobulin replacement therapy • Genetic Testing • Surveillance for autoimmunity and malignancy
  71. 71. …THANK YOU…

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