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Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID)
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Common variable immunodeficiency (CVID)

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Common variable immunodeficiency (CVID) …

Common variable immunodeficiency (CVID)

Presented by Jaichat Mekaroonkamol, MD.

September20, 2013

Published in: Health & Medicine, Technology
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  • We performed a historical cohort study
    to describe the epidemiology of PIDs in Olmsted County, Minnesota,
    during a 31-year period from January 1, 1976, through
    December 31, 2006, using the Rochester Epidemiology Project.
    Incidence and trends over time, presence of comorbid conditions,
    and trends in management were determined.
  • B cell develop in BM from hematopoietic stem cell through rearrangement of Ig heavy chain and light chain and initial selection of repertoire with selection against autoreactive B cell.
    Mature B cell express both IgM and IgD export from BM and enter secondary lymphoid organ
    Affinity maturation take place through somatic hypermutation of variable region gene in germinal center of secondary lymphoid follicle where isotype class switching take place, enable production of IgG IgA IgE
    B cell selected through affinity maturation become memory B cell or long lived plasma cell that home back to BM and produce high-affinity Ab.
  • B cell develop in BM from hematopoietic stem cell through rearrangement of Ig heavy chain and light chain and initial selection of repertoire with selection against autoreactive B cell.
    Mature B cell express both IgM and IgD export from BM and enter secondary lymphoid organ
    Affinity maturation take place through somatic hypermutation of variable region gene in germinal center of secondary lymphoid follicle where isotype class switching take place, enable production of IgG IgA IgE
    B cell selected through affinity maturation become memory B cell or long lived plasma cell that home back to BM and produce high-affinity Ab.
  • B cell develop in BM from hematopoietic stem cell through rearrangement of Ig heavy chain and light chain and initial selection of repertoire with selection against autoreactive B cell.
    Mature B cell express both IgM and IgD export from BM and enter secondary lymphoid organ
    Affinity maturation take place through somatic hypermutation of variable region gene in germinal center of secondary lymphoid follicle where isotype class switching take place, enable production of IgG IgA IgE
    B cell selected through affinity maturation become memory B cell or long lived plasma cell that home back to BM and produce high-affinity Ab.
  • B cell develop in BM from hematopoietic stem cell through rearrangement of Ig heavy chain and light chain and initial selection of repertoire with selection against autoreactive B cell.
    Mature B cell express both IgM and IgD export from BM and enter secondary lymphoid organ
    Affinity maturation take place through somatic hypermutation of variable region gene in germinal center of secondary lymphoid follicle where isotype class switching take place, enable production of IgG IgA IgE
    B cell selected through affinity maturation become memory B cell or long lived plasma cell that home back to BM and produce high-affinity Ab.
  • B cell develop in BM from hematopoietic stem cell through rearrangement of Ig heavy chain and light chain and initial selection of repertoire with selection against autoreactive B cell.
    Mature B cell express both IgM and IgD export from BM and enter secondary lymphoid organ
    Affinity maturation take place through somatic hypermutation of variable region gene in germinal center of secondary lymphoid follicle where isotype class switching take place, enable production of IgG IgA IgE
    B cell selected through affinity maturation become memory B cell or long lived plasma cell that home back to BM and produce high-affinity Ab.
  • B cell develop in BM from hematopoietic stem cell through rearrangement of Ig heavy chain and light chain and initial selection of repertoire with selection against autoreactive B cell.
    Mature B cell express both IgM and IgD export from BM and enter secondary lymphoid organ
    Affinity maturation take place through somatic hypermutation of variable region gene in germinal center of secondary lymphoid follicle where isotype class switching take place, enable production of IgG IgA IgE
    B cell selected through affinity maturation become memory B cell or long lived plasma cell that home back to BM and produce high-affinity Ab.
  • PID tertiary paediatric centre in South Africa.
    retrospective study: 16 pts diagnosed with PID from 1983 - 2009.
    Results: Ab deficiencies predominated(51%) followed by well-defined syndromes(24%).
    Common variable immunodeficiency was commonest antibody deficiency.
    mean age of diagnosis was 51 mo overall but decreased significantly to 35 mo over the last 9 yrs.
  • The age at diagnosis shows 2 peaks, between 6 and 10 years of age and in young
    adulthood (between 26 and 40 years)
    (Gadola S, Salzer U, Schultz H, Grimbacher B. Adult-onset primary immunodeficiencies.
    Der Internist 2004;45:912-22)
  • Figure 1: Organ systems involved in the pathogenesis of CVID
    Left: healthy organs. Right: organ-system involvement. Patients also have increased risk of neoplasia, rheumatoid arthritis, vitiligo, and other autoimmune diseases.
    Reproduced with permission from the Mayo Foundation for Medical Education and Research
  • Criteria for possible or probable CVID diagnosis established by international concensus statement
  • When
    immunoglobulin (Ig) levels are reduced, further evaluation
    is indicated to rule out secondary causes of hypogammaglobulinemia
    ( table 2 ) [14, 25] , while normal Ig
    levels should prompt evaluation for alternative immune
    defects, such as complement deficiencies, that may mimic the clinical presentation of Ig defects
  • Before Dx CVID chronic or recurrent infection present in majority of Pt. Most pt affected with infection of upper and lower RS tract.
  • Prospective enroll adult pt 2004-2007 with PID ,341 enroll 252 is CVID
    Median age of first symptom was 19 yr
    Median age at CVID dx was 33.9 yr
  • Median delay of Dx was 6.9 yr(0-55 yr)
    15.6 yr for 138 pt whom initial symptom before 1990
    2.9 yr for 114 pt whom initial symptom after 1990
    Median delay of Dx was 14 yr: pt whom initial symptom before 15 yr
    3.7 yr: pt whom initial symptom after 15 yr
  • Report of a very large cohort of CVID patients focusing on complications,
    morbidity, mortality, and potential biomarkers that may predict outcomes.
  • Figure 1. Autoimmunity in CVID. Of 473 patients with CVID,
    134 (28.6%) had autoimmunity.6 The main autoimmune diseases are
    shown here. In the category “other” are included neutropenia, pernicious
    anemia, anticardiolipin Ab, antiphospholipid syndrome, diabetes mellitus,
    juvenile rheumatoid arthritis, uveitis, multiple sclerosis, systemic lupus
    erythematosus, autoimmune thyroid disease, lichen planus, vasculitis,
    vitiligo, and psoriasis. ITP indicates immune thrombocytopenia; AIHA,
    autoimmune hemolytic anemia; RA, rheumatoid arthritis.
  • 240 pt had RS symptom, pneumonia report in 147 pt:S. pneumoniae, H. influenzae document in 46 and 17 case
    Recurrent and chronic diarrhea report in 118 pt: giardia =35, salmonella=19,campylobacter=19
  • Up to 73% of CVID
    patients develop chronic structural pulmonary complications, of which
    bronchiectasis and bronchial wall thickening are most frequently
    detected. HRCT is the most sensitive method for identification of
    structural abnormalities, detecting pulmonary complications that were
    missed on CXR and PFT in 2–59% of patients
    On PFT, obstructive
    flow-volume curves were most commonly found, eventually occurring in
    50–94% of patients. HRCT is an important diagnostic tool for
    pulmonary complications in CVID at the time of diagnosis and at
    regular time-points during follow-up, with the proper follow-up interval
    yet to be determine
  • Report of a very large cohort of CVID patients focusing on complications,
    morbidity, mortality, and potential biomarkers that may predict outcomes.
  • 62 CVID perform SPT , specific IgE for aeroallergen and bronchial provocation with histamine and allergen.
  • Most common was obstructive lung disease in 29(47.5%) of 62 pt.
    18(29%) of 62 pt clinical suggest allergic asthma
  • Asthma diagnosed in 9 (14.5%)pt and atopy had 6, allergic ashma diagnosed in 4 pt.
    CVID testing negative for specific IgE Ab and suspected allergic asthma presented positive response to bronchial provocation test with allergen.
  • Autoimmune disease up to 25%, mostlyITP, AIHA or evan syndrome, autoimmune neutropenia
  • because of uncontrolled autoimmunity
    (ie, immune thrombocytopenia or autoimmune hemolytic
    anemia), a significant proportion of CVID patients have had a
    splenectomy
  • Report of a very large cohort of CVID patients focusing on complications,
    morbidity, mortality, and potential biomarkers that may predict outcomes.
  • Report of a very large cohort of CVID patients focusing on complications,
    morbidity, mortality, and potential biomarkers that may predict outcomes.
  • Figure 2. Gastrointestinal lymphoid nodules. (A) A 50-year-old woman who had a
    history of a duodenal ulcer, now resolved. She had a repeat gastroscopy for
    symptoms of gastritis; H pylori was not found. The mucosa of the stomach folds of this
    female patient contained numerous lymphoid follicles. (B) The jejunum of a 28-yearold
    male patient containing massive nodules of lymphoid hyperplasia; he had
    experienced a 20-lb weight loss.
  • Report of a very large cohort of CVID patients focusing on complications,
    morbidity, mortality, and potential biomarkers that may predict outcomes.
  • Incidence of malignancy 15% of subject. 5 fold increase in cancer, excess of stomach cancer (47 fold), NHL (30 fold)
    Cohort of 476 pt, 3 stomach cancer(0.6%), 32 NHL(6.7%) and 4 case of HD
  • Report of a very large cohort of CVID patients focusing on complications,
    morbidity, mortality, and potential biomarkers that may predict outcomes.
  • Report of a very large cohort of CVID patients focusing on complications,
    morbidity, mortality, and potential biomarkers that may predict outcomes.
  • The European Common Variable Immunodeficiency
    Disorders registry was started
    in 1996 to define distinct clinical phenotypes
    and determine overlap within individual
    patients.Atotal of 7 centers contributed
    patient data, resulting in the largest
    cohort yet reported. Patients (334), validated
    for the diagnosis, were followed for
    an average of 25.6 years (9461 patientyears).
  • The risk of death in this interval was nearly
    11 times higher for CVID patients with 1 or more of the noninfectious
    complications than for subjects who had infections only
  • However, we found here that not all complications
    were associated with reduced survival. Patients with gastrointestinal
    disease (HR 2.78; P .0004); liver diseases and hepatitis
    (HR 2.48; P .0003); lymphoma (HR 2.44; P .001);
    chronic lung disease, including radiologic or functional lung
    disease, or both as described here (HR 2.06; P .001); or
    malabsorption (HR 2.06; P .022) had reduced survival in this
    interval, compared with CVID patients without these particular
    complications. In contrast, patients with any of the autoimmune
    conditions, cancers other than lymphoma, history of splenectomy,
    presence of granulomatous disease, or the development of bronchiectasis
    alone did not have significantly reduced survival over the
    4 decades of study.
  • With data collected by the immunology laboratory and
    the immunodeficiency clinic, all patients with confirmed or
    presumed clinical or laboratory diagnosis of CVID between
    1990 and 2004 were identified
    Of the 32 remaining patients included as primary
    CVID, 15 were male and 17 were female. Median age at
    diagnosis was 10.4 4.3 years (range 1.1 to 17.4 years). Age
    distribution showed highest incidence at 4, 9 and 15 to 16
    years of age. All patients were Caucasians of European origin.
    All included patients were alive at the time of evaluation
  • (A) European cohort: serum immunoglobulin isotypes at diagnosis. Patients are divided into four groups depending on their presenting IgA
    level. Each group is further subdivided according to the IgM level, with those with the lowest IgM levels (£0Æ1 g/l) in the first column; those with the
    highest IgM (>0Æ5 g/l) in the third column and those with IgM levels between (0Æ1–0Æ5 g/l) in the second column. Each column is divided into three,
    depending on the IgG level; those in the lower section with IgG £1Æ0 g/l; those with IgG > 3Æ0 £ 6Æ5 g/l at the top and those with IgG 1Æ1–3 g/l in the
    middle. The number of patients in each group is in each box and plotted on the y-axis. This research was originally published in Blood. Chapel, H.,
    Lucas, M., Lee, M., Bjorkander, J., Webster, D., Grimbacher, B., Fieschi, C., Thon, V., Abedi, M.R., Hammarstrom, L. (2008) Common variable
    immunodeficiency disorders: division into distinct clinical phenotypes. Blood 2008, 112, 277–286. the American Society of Hematology. (B) United
    States Cohort: Serum Immunoglobulin isotypes at diagnosis. Similar to Figure 1a, 349 subjects from one medical centre (Mount Sinai, NYC) are
    divided into the same categories based on presenting serum immunoglobulin levels.
  • Lymphocyte subset distribution in pediatric CVID-patients at
    first diagnosis: Normal percentage for CD4 T-cells (41.2 10.9),
    CD8 T-cells (26.5 8.5), natural killer cells (7.5 3.6). B-cells within
    lower normal range (9.7 6.6). Boxes represent 25th, 50th and 75th
    percentile, range bars show 10th and 90th percentile, and black circles
    represent 5th and 95th percentile. Dotted line represents the geometric
    mean.
  • CD19 :pan B cell marker
    CD27: memory phenotype and presence or absence of IgM and IgD
    CD38 and IgM distinguish transitional B cell and plasmablast
    CD21: marker for B cell activation and expressed on mature B cell
  • CD19 :pan B cell marker
    CD27: memory phenotype and presence or absence of IgM and IgD
    CD38 and IgM distinguish transitional B cell and plasmablast
    CD21: marker for B cell activation and expressed on mature B cell
  • CD19 :pan B cell marker
    CD27: memory phenotype and presence or absence of IgM and IgD
    CD38 and IgM distinguish transitional B cell and plasmablast
    CD21: marker for B cell activation and expressed on mature B cell
  • CD19 :pan B cell marker
    CD27: memory phenotype and presence or absence of IgM and IgD
    CD38 and IgM distinguish transitional B cell and plasmablast
    CD21: marker for B cell activation and expressed on mature B cell
  • Genetic defect in CVID, defect in 4 gene
    ICOS( inducible T cell costimulator)
    Deficiency of ICOS expressed on T cell
    9 pt c mutation in ICOS present with recurrent bacterial infection, splenomegaly, autoimmune neutropenia, intestinal lymphoidhyperlasia, neoplasia
    Low peripheral B cell
    Few/no class switched B cell, hypogammaglobulinemia
    T cell from ICOS deficient produce very little IL10, asso defective formation of germinal center leading to impaire B cell memory
    AR
    ICOS upregulate on both CD4 and CD8 effector and memory T cell and activated NK cell & enhance NK cell function
    ICOS express in geminal center and T cell zone of spleen, LN, peyer patch
    Tumor necrosis factor superfamily
    Mutation in TACI, protein encoded by TNFRSF13B, asso c lymphoproliferation include splenomegaly or tonsillar hyperplasia, IgA def with autoimmune thyroiditis
  • Molecule implicated genetic studied of CVID
    A: ICOS is positive costimulator (expressed CD28)enable T cell interaction with B cell, monocyte and DC
    B: BAFF-R and TACI are cell surface receptor TNF receptor family play part in B cell differentiation and function.
    BAFF-BAFF-R interaction provide differentiation of peripheral B cell.
    Role of BAFF-TACI interaction – TACI signal intracellular through TNF receptor associated factor(TRAF) induce factor k B activation
    TACI also interact intracellular with calcium modulator and cyclophilin ligand(CAML) interaction with APRIL, TACI regulate isotype switching if Ig and Ab response to T-independent Ag
    C: CD19 is B cell specific cell surface marker, that is part of B cell coreceptor along with CD21 and CD81, CD19 expressed throughout B cell maturation from pro B cell through to plasmablast, coligation of B cell receptor ( BCR) with coreceptor complex of CD19-CD21-CD81 increase B cell signalling.
  • Prospective cohort 90 pt confirmed CVID Oxford UK LA follow up 22 yr
    Number type and severity of infection in CVID , red bar are propation of infection type that classified as severe
  • In my view, for continued lung disease, daily
    antibiotic prophylaxis (trimethoprim sulfa, or possibly better,
    macrolides, which provide substantial anti-inflammatory effects26)
    provide more benefit than much greater doses of Ig therapy.
    Although the rotation of antibiotics to discourage resistant organisms
    often is used in immune-competent patients with chronic lung
    disease, I have not found it necessary to rotate antibiotics in CVID;
    resistant organisms can be treated if they arise
  • Transcript

    • 1. King Chulalongkorn Memorial Hospital Common variable immunodeficiency Jaichat Mekaroonkamol, MD. L/O/G/O
    • 2. Outlines Common variable immunodeficiency: CVID 1 Epidemiology 2 Pathophysiology 3 Clinical phenotype 4 Genetic defects 5 Management
    • 3. Prevalence • PID are rare and have an overall prevalence of approximately 1:5001:10,000 live births • However, a much higher rate is observed among populations with high consanguinity rates or among genetically isolated populations Elsevier Saunders, 2004 J Allergy Clin Immunol ,2010
    • 4. Incidence and trends of PID Mayo Foundation for Medical Education and Research, 2009
    • 5. Family history of PID • 17% in the 2007 survey • 22% in the 2002 survey • 24% in the 1996/97 survey.
    • 6. • 4.5% reported a family history of primary immunodeficiency disease • 16.4% reported a family history of death at young age • 9% reported consanguineous marriage J Clin Immunol, 2009
    • 7. Male to female ratio was 1.9 J Clin Immunol, 2009
    • 8. Overall percentage distribution of various types PIDs Mayo Foundation for Medical Education and Research, 2009
    • 9. 52.2% 25.4% 10.4% 12% J Clin Immunol, 2009
    • 10. J Clin Immunol, 2009
    • 11. When to suspect immunodeficiency If infections are •Chronic •Recurrent •Unusual •Invasive •Severe Then •Evaluate
    • 12. 10 warning signs 16
    • 13. 10 warning signs: adult (>18 year old) 17
    • 14. B-cell development and differentiation
    • 15. 1. B cell receptor gene Rearrangement 2. Receptor editing and negative selection
    • 16. Lancet 2008; 372: 489–502
    • 17. 1. PRO B cell - No surface immunoglobuliin/ B cell receptor Lancet 2008; 372: 489–502
    • 18. 2. PRE B cell - RAG: Recombination activating gene - TdT: Terminal deoxynucleotidyl transferase - µ chain + surrogate light chain(λ5) = Pre B cell receptor Lancet 2008; 372: 489–502
    • 19. 3. Immature B cell - µ chain + light chain(κλ) = B cell receptor: IgM Lancet 2008; 372: 489–502
    • 20. Recognized self antigen 1.Receptor editing 2.Negative selection 3.Functional unresponsiveness Selective polyadenylation and alternative splicing of constant gene Mature B cell: IgM + IgD Lancet 2008; 372: 489–502
    • 21. Lancet 2008; 372: 489–502
    • 22. 26
    • 23. Lancet 2008; 372: 489–502
    • 24. 14% J Clin Immunol, 2009
    • 25. Common variable immune deficiency disorders • Prevalence 1 in 25,000 to 1 in 50,000 • Most patients are diagnosed between the ages of 20 and 40 years – but approximately 20% are under the age of 20 Cunningham-Rundles C. Blood. 2012.
    • 26. CVID: Clinical phenotype Lancet 2008; 372: 489–502
    • 27. Clinical complication Charlotte Cunningham-Rundles. Blood. 2010;116(1):7-15
    • 28. RS 86%
    • 29. CVID: Definition • Reduced serum IgG, IgA and/or IgM, by at least 2 SDs below the mean for age • Poor or absent antibody production to both protein and carbohydrate vaccines • Exclusion of other causes of hypogammaglobulinemia Clin Immunol. 1999 Curr Allergy Asthma Rep. 2001 Clin Immunol. 2009 Blood. 2010
    • 30. British Journal of Haematology, 2009
    • 31. Bacterial infection (RS/GI) CVID XLA HIM SIgAD OI Enlarge LN Auto immune CD19 √ √ √ √ X X √ X possible √ X √ vary X possible possible possible ↓ ↔ ↔ YU-Lung Lau, Hong Kong. APAPARI, 2013
    • 32. www.themegallery.com
    • 33. Average delay of 6-7 years in diagnosis Cunningham-Rundles C. Blood. 2012 www.themegallery.com
    • 34. www.themegallery.com
    • 35. Clinical Infectious Diseases 2008; 46:1547–54
    • 36. Median age of first symptom was 19 yr Median delay of Dx was 6.9 yr (0-55 yr) Median age at CVID diagnosis was 33.9 yr Clinical Infectious Diseases 2008; 46:1547–54
    • 37. Delay between first symptom and diagnosis of CVID 15.6 yr for 138 patients 2.9 yr for 114 patients 14 yr 3.7 yr Clinical Infectious Diseases 2008; 46:1547–54
    • 38. Clinical Infectious Diseases 2008; 46:1547–54
    • 39. CVID: Clinical phenotype • 473 subjects with CVID - 208 males and 265 females • Cohort study: 1974-2010 • The diagnosis of CVID was made by standard criteria Resnick et al. Blood. 2012;119:1650-1657
    • 40. 68% had one or more of the inflammatory/autoimmune complication Resnick et al. Blood. 2012;119:1650-1657
    • 41. Autoimmune disease Patients (n) F/U (years) autoimmune ESID 334 25.5 12-46% US 473 40 28.6% France 69 40 20% Cunningham-Rundles C. Blood. 2012.
    • 42. Autoimmune disease Resnick et al. Blood. 2012;119:1650-1657
    • 43. Clinical complication Charlotte Cunningham-Rundles. Blood. 2010;116(1):7-15
    • 44. www.themegallery.com
    • 45. • 26 articles including 587 patients with CVID • 73 % develop chronic structural pulmonary complications: – Bronchiectasis – Bronchial wall thickening • HRCT is the most sensitive method – CXR and PFT miss in 2–59% of patients • Obstructive flow-volume curves found in 50 - 94 % of patients(Child>Adult) Pediatr Allergy Immunol 2010
    • 46. • Chronic lung disease : 28.5% • leading to radiographic changes with or without functional impairment • equally in males and females • Bronchiectasis: 11.2% • Progressive lung disease led to the need for chronic oxygen therapy: 6.1% Resnick et al. Blood. 2012;119:1650-1657
    • 47. Allergic diseases • 38 % of pts in one of cohorts had some evidence of an allergic disease: food allergy, eczema, urticaria, rhinitis, asthma. J Pediatr. 2009;154(6):888.
    • 48. Autoimmune disease • Autoimmunity is seen in 20 - 25 % of CVID. • Autoimmune cytopenias are more common presenting disorder in children than adults. • DM, psoriasis, SLE, RA, JIA Charlotte Cunningham-Rundles. Blood. 2010;116(1):7-15
    • 49. Because of uncontrolled autoimmunity (ITP/AIHA) Resnick et al. Blood. 2012;119:1650-1657
    • 50. Gastrointestinal problems 15.4% 5.9% 4.2 % 1.9 % 1.3% 1.1% <1% Resnick et al. Blood. 2012;119:1650-1657
    • 51. Granulomatous disease 9.7 % Resnick et al. Blood. 2012;119:1650-1657
    • 52. Malignancy 8.2 % non-Hodgkin B-cell lymphomas were the most common 59 % Resnick et al. Blood. 2012;119:1650-1657
    • 53. Malignancy 7% Resnick et al. Blood. 2012;119:1650-1657
    • 54. Neurodegenerative diseases or encephalopathy • Adults with CVID, enteroviral and JE virus infection can cause neurodegeneration. • Enteroviral infection has not described in pediatric CVID. • In contrast, neurodegenerative diseases described in other pediatric immunodeficiencies (esp. X-linked agammaglobulinemia) Ann Allergy Asthma Immunol. 2007;98(5):483
    • 55. Complication VS Outcome P <0 .0001 Helen Chapel et.al, Blood, 2008
    • 56. Helen Chapel et.al, Blood, 2008
    • 57. Complication VS Outcome hazard ratio [HR] = 10.96 P <0 .0001 Kaplan–Meier survival curves for CVID patients with infections only versus those with any other complication Resnick et al. Blood. 2012;119:1650-1657
    • 58. Resnick et al. Blood. 2012;119:1650-1657
    • 59. HOW TO EARLY DIAGNOSIS
    • 60. J Pediatr 2009;154:888-94
    • 61. J Pediatr 2009;154:888-94
    • 62. J Pediatr 2009;154:888-94
    • 63. • 10% of patients with remarkably low levels of immunoglobulins may be infection free. – ITP – AIHA – Sarcoid-like picture • check specific antibody production in such patients – Adult-onset ITP and AIHA Arnold et al, 2008
    • 64. Lancet 2008; 372: 489–502
    • 65. Lancet 2008; 372: 489–502
    • 66. Peripheral blood B-cell subsets Lancet 2008; 372: 489–502
    • 67. Peripheral blood B-cell subsets • Low in 50–75% of CVID • Associated with • granulomatous disease • Splenomegaly • Autoimmune cytopenias • Bronchiectasis Lancet 2008; 372: 489–502
    • 68. • Absence: Associated with Peripheral blood B-cell • Recurrent bacterial pneumonia • Bronchiectasis subsets Lancet 2008; 372: 489–502
    • 69. Peripheral blood B-cell subsets • Increases: Associated with • Lymphadenopathy • Splenomegaly Lancet 2008; 372: 489–502
    • 70. Lancet 2008; 372: 489–502
    • 71. Genetic defects in CVID
    • 72. Genetic defects in CVID • ICOS: CVID inducible T cell costimulator • CD19 • TACI – (TNFRSF13B: tumour necrosis factor receptor superfamily, member 13B) • BAFF-R – (TNFRSF13C: tumour necrosis factor receptor superfamily, member 13C ) Lancet 2008; 372: 489–502
    • 73. Genetic defects in CVID Lancet 2008; 372: 489–502
    • 74. ICOS Deficiency • 2% of patients with CVID • Autosomal recessive trait • Serum IgG and IgA levels were markedly reduced in all patients – IgG<1.9-2.55 g/L – IgA<0.06-0.58g/L – Serum IgM level • reduced in 6/9 patients • low normal values in 3/9 patients C.Bacchellietal.Clinical and Experimental Immunology2007, 149:401–409
    • 75. www.themegallery.com
    • 76. Nature Reviews Immunology, 2012
    • 77. C.Bacchellietal.Clinical and Experimental Immunology2007, 149:401–409
    • 78. TACI mutation • 10-20% of CVID patients • Associated with – Lymphoproliferation • Splenomegaly • Tonsillar hyperplasia • Follicular nodular hyperplasia of GI – Autoimmunity • Hemolytic anaemia • Autoimmune thrombocytopaenia • Thyroiditis Lancet 2008; 372: 489–502
    • 79. Basic Science Research , 2013
    • 80. www.themegallery.com
    • 81. www.themegallery.com
    • 82. BAFF-R Deficiency Lancet 2008; 372: 489–502
    • 83. www.themegallery.com
    • 84. CD 19 deficiency • 4 patients with homozygous mutations in CD19, from 2 unrelated families – Hypogammaglobulinemia – Increased susceptibility to infection – Normal numbers of CD20+ B cells – Expression of CD 19 on B cell • Undetectable in ¼ patients • Rarely detectable in ¾ patients Lancet 2008; 372: 489–502
    • 85. CD 19 deficiency • Decrease numbers of CD27+ memory B cells & CD5+ B cells • Poor antibody response to rabies vaccination • Normal germinal center formation • No autoimmune features or signs of lymphoprolipheration Lancet 2008; 372: 489–502
    • 86. www.themegallery.com
    • 87. Management
    • 88. Management • • • • Ig replacement Antimicrobial drugs Complications and management Organ and stem cell transplantation
    • 89. Charlotte CunninghamRundles. Blood,2010
    • 90. usually in doses of 400 to 600 mg/kg body weight per month IV/SC Charlotte Cunningham-Rundles. Blood,2010
    • 91. Ig replacement • • • • Every 2 weeks for SC route Every 3 or 4 weeks for IV route Iodinated IgG protein: half-life 21 days Current intravenous Igs have half-lives closer to 30 days • Administered IgG in CVID subjects with chronic lung or gastrointestinal disease appears to have a shorter half-life Charlotte Cunningham-Rundles. Blood,2010
    • 92. Ig replacement • Goal: to prevent infections • The target trough serum IgG varies depending on the baseline level of IgG – baseline serum IgG of less than 100 mg/dL, : at least 600 mg/dL – No functional antibody : at least 900 mg/dL to supply the minimum “normal” level of functional Ig – Serum IgG levels measured at 6- to 12month intervals Int Arch Allergy Immunol 2009;150:311–324 Charlotte Cunningham-Rundles. Blood,2010
    • 93. Ig replacement Most patients with CVID have little or no serum IgA Anti IgA antibody? Low-IgA preparations? Testing for anti-IgA IgE? Lancet 2008; 372: 489–502 Int Arch Allergy Immunol 2009;150:311–324 Charlotte Cunningham-Rundles. Blood,2010
    • 94. Antimicrobial drugs • Sinopulmonary infections – Fluoroquinolones – Amoxicillin clavulanate Lancet 2008; 372: 489–502
    • 95. Complications and management • Chronic lung disease – Greater doses of Ig (600 mg/kg/month) – Daily antibiotic prophylaxis • Bactrim • Macrolides: anti-inflammatory effects Int Arch Allergy Immunol 2009;150:311–324 Charlotte Cunningham-Rundles. Blood,2010
    • 96. Complications and management • Granulomatous/lymphoid infiltrative disease – Oral steroids 10-20 mg a day every other day may preserve lung or liver function – 200 to 400 mg a day ( 3.5-6.5 mg/kg) of hydroxycloroquine – Pulmonary granuloma • twice daily inhaled beclomethasone Charlotte Cunningham-Rundles. Blood,2010
    • 97. Complications and management • Autoimmune disease – Greater doses of Ig (1 g/kg body weight) given weekly for a short time – Intravenous steroids (1 g of methylprednisolone) followed by moderate doses of oral steroids tapered over several weeks: ITP/AIHA – Rituximab in standard doses for more refractory or recurrent ITP and/or AIHA – Splenectomy is to be avoided Charlotte Cunningham-Rundles. Blood,2010
    • 98. Complications and management • Gastrointestinal disease – Initial treatment is determined on the basis of culture results, biopsy findings • Antibiotics • Restoration of nutrients • Rehydration Charlotte Cunningham-Rundles. Blood,2010
    • 99. Organ and stem cell transplantation • There are a few reports of liver and lung transplant in CVID, with at least shortterm survival but overall variable outcome Charlotte Cunningham-Rundles. Blood,2010
    • 100. Monitoring patients over time Charlotte Cunningham-Rundles. Blood,2010
    • 101. Survival P< 0.0001 87% of the cohort F/U 19.6% had died The median age at death was - 44 years for females(10-90yr) - 42 years for males(9-79 yr) Resnick et al. Blood. 2012;119:1650-1657
    • 102. L/O/G/O

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