Criteria for possible or probable CVID diagnosis established by international concensus statement
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 organAffinity 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.
CD19 :pan B cell marker CD27: memory phenotype and presence or absence of IgM and IgDCD38 and IgM distinguish transitional B cell and plasmablastCD21: marker for B cell activation and expressed on mature B cell
Flow cytometryPBMC gating on lymphocyteB cell marker CD191)Naive IgD+ IgM+ CD27- Bcell2)Marginal zone B cell: IgD+ IgM+CD27+:less effect3)Switch memory B cell: IgD- IgM-CD27+: ลดลง4)CD38 low CD21low:found in auto5)CD38++IgMhi transitional B cell6)CD38+++IgM- plasmablast: reduce in CVID
The most significant dysregulation of B cell subpopulation Pt with splenomegaly: tend to lower % B cell, MZ B cell, switch memory B cellBest marker for splenomegaly is increase CD21 low B cell(b) Lymphadenopathy: asso increase transitional B cellGranulomatous disease: connected with severe reduction of switch memory B cell
Comparison of scheme: 303ptParis: reduction of both CD27+ b cell < 11% (MB0) = 48% at least of swicth memory B cell (MB1) = 43 % nearly normal CD27+ B cell (MB2) = 9% significant increase splenomegaly in gr MB0(47%) compare with MB2(23%) granulomatous dZ more common in MB0 than MB1 absent in MB2Freiburg: gr1(77%) ↑ CD21 low=gr1a gr 2 (23%) splenomegaly significant increase in gr1a compare with gr1b granulomatous Dz common in gr1a 20% than gr2
≤1% B cell (gr B-)>1% B cell (gr B+) B+ แบ่งเป็น smB - ≤2% switched memory B cell smB + >2% switch memory B cellSevere reduction of class switched B cell asso with significant decrease serum IgGsplenomegaly and granulomatous dz increase in smB –smB-Trhi≥ 9% transitional B cell: lymphadenopathy
Expansion of CD21low B cell above 10% of B cell designated 21loExpansion of CD21low B cell significant more common in gr smB- than gr smB+Incidence of splenomegaly increase in smB-21low compare with CD21norGranulomatous dZ common in smB-21low, absent in smB+21norsmB+21lo more common c splenomegaly than smB+21 norGranulomatous dZ common in smB21 lo, nearly absent in smB+21nor
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.
Prospective enroll adult pt 2004-2007 with PID ,341 enroll 252 is CVIDMedian age of first symptom was 19 yrMedian 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 19902.9 yr for 114 pt whom initial symptom after 1990Median delay of Dx was 14 yr: pt whom initial symptom before 15 yr 3.7 yr: pt whom initial symptom after 15 yr
IgG: circle, IgM:triangle, IgA:diamondUpper chart: line 3 percentile of normal IgGLower chart: : line 3 percentile of IgM and IgA
Lymphocyte subset distribution in CVID at first diagnosis.Normal percent for CD4+T cell, CD8+T cell, NK cellB cell within lower normal range
Lt: healthy organRt: organ system involvement. Pt also have increased risk of neoplasia, RA, vitiligo, autoimmune disease
French national study prospective enroll 2004-2007, 341 enrolled, 252 dx CVIDMost frequent initial symtom were URI: bronchitis, sinusitis, pneumonia and/or bronchiectasis
Respiratory tract is most common involved 73% of pt attributable to S.pneumonia, H.influenza, mycoplasmaSevere bacterial infection such as empyema, sepsis, meningitis,osteomyelitis, often same orgainism, are less common.Current cohort , 90% of 476 had ≥ 1 infectious complication
European cohort 303 CVID demonstrate strong association among granulomatous inflammation, autoimmune phenomena and splenomegalyGranulomatous disease is almost exclusively detected in pt with splenomegaly(28/33 pt, P < 0.001)Autoimmune cytopenia, other autoimmune phenomena, lymphadenopathy significant associated with splenomegalySignificant coincidence of autoimmunity and other autoimmune phenomena with granulomatous disease3 pt, granulomatous disease and autoimmune cytopenia in absent of splenomegaly
240 pt had RS symptom, pneumonia report in 147 pt:S. pneumoniae, H. influenzae document in 46 and 17 caseRecurrent and chronic diarrhea report in 118 pt: giardia =35, salmonella=19,campylobacter=19
Prospective cohort 90 pt confirmed CVID Oxford UK LA follow up 22 yrNumber type and severity of infection in CVID , red bar are propation of infection type that classified as severe
Before Dx CVID chronic or recurrent infection present in majority of Pt. Most pt affected with infection of upper and lower RS tract.
Lymphocytic pulmonary infiltrationA: 40 yr woman gradually worsening severe lung disease. CT chest revealed massive infiltrative composed of lymphocytic collection and fibrotic scarB: biopsy, infiltration T cell in lung, obliterating normal architecture.
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
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
Genetic defect in CVID, defect in 4 geneICOS( inducible T cell costimulator)Deficiency of ICOS expressed on T cell9 pt c mutation in ICOS present with recurrent bacterial infection, splenomegaly, autoimmune neutropenia, intestinal lymphoidhyperlasia, neoplasiaLow peripheral B cellFew/no class switched B cell, hypogammaglobulinemiaT cell from ICOS deficient produce very little IL10, asso defective formation of germinal center leading to impaire B cell memoryARICOS upregulate on both CD4 and CD8 effector and memory T cell and activated NK cell & enhance NK cell functionICOS express in geminal center and T cell zone of spleen, LN, peyer patchTumor necrosis factor superfamilyMutation in TACI, protein encoded by TNFRSF13B, asso c lymphoproliferation include splenomegaly or tonsillar hyperplasia, IgA def with autoimmune thyroiditis
Molecule implicated genetic studied of CVIDA: ICOS is positive costimulator (expressed CD28)enable T cell interaction with B cell, monocyte and DCB: 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 activationTACI 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 AgC: 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.
ICOS and CD19 deficiency Defect in TACI, BAFF-R and MSH5 remain within CVID
Prospective cohort 90 CVID in oxford UK F/U 22 yrDisease related phenotype result administration high dose IVIG compare with no disease complicationPt with enteropathy, cytopenia, polyclonal lymphoproliferation treated with high dose IVIG to prevent infection.Lymphoid malignancy also received higher replacement replacement of IgOrgan specific autoimmunity no significant different dose of IVIGPolyclonal lymphoproliferative & LIP receive significant higher dose of IVIG
Mean trough IgG level to keep pt infection-free.Red bar: CVIDBlue bar: XLA3 different threshold of infection: annual infection score ≤ 4.5, ≤ 2.5, 0Wide range of trough IgG level were infection freeXLA display large range of IgG to maintain infection free stateTrough level to prevent infection higher in XLA compared with CVIDDose range 0.2-1.2 g/kg/mo
Significant higher mean trough IgG in 2000s compare with 1980s and 1990sSignificant increase dose of IVIG 0.51±0.81 g/kg/mo in 1980s to 0.58 ± 0.28 in 1990s and 0.57± 0.24 in 2000s
Most pt carry out all normal activity, regual schedule and careful follow upStable pt seen at least yearly interval, aforementioned complication shorter interval such as 3-6 month Routine monitor subject for lung disease no current consensus, HRCT baseline referralRadiosensitive demonstrate in CVIDCVID c chronic cough and/or lung damage prefer LFT;carbon monoxide diffusion, HRCT at 3-4 yr intervalMonitor for autoimmune not require cause CBC & medical oversightRoutine endonot requireIssue of enlarge LN: biposy may be required, lymphoma are extre nodal and appear in unusal location lung or mucosal associated tissue
1. Common variable immunodeficiency<br />Sasikarn Suesirisawad, MD<br />
2. DEfinition<br /><ul><li>Presence of hypogammaglobulinemia of two or more immunoglobulin isotype (low IgG, IgA, or IgM)
3. Recurrent sinopulmonary infection
4. Impaired functional antibody responses
5. Absent isohaemagglutinin
6. Poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines(S. pneumoniae)
7. Other finding: autoimmunity, granulomatous disease, and neoplasia</li></li></ul><li>
11. Flow cytometry B cell subpopulation<br />
12. Association of clinical phenomena with dysregulated B cell subpopulations<br />
13. Evaluation of the Paris and Freiburg classification scheme.<br />P<0.001<br />P=0.03<br />P=0.04<br />P=0.02<br />P=0.02<br />
16. TCELL AND CELLULAR ABNORMALITIES<br /><ul><li>Decreased T lymphocyte proliferation to mitogens and Ag (40 % of patients)
17. ClinImmunol. 1999;92(1):34.
18. Low CD4/CD8 T cell ratio due to decrease in CD4 or increase CD8
19. Reduced T regulatory cells
20. ClinExpImmunol. 2009;156(3):446.
21. ClinImmunol. 2009;131(2):240.</li></li></ul><li>EPIDEMIOLOGY <br /><ul><li>Usually diagnosed in the second or third decade of life.
22. 25 % of all CVID pts present in childhood or adolescence, earlier peak of diagnosis at 8 yrs of age. </li></ul>An Pediatr (Barc). 2011;74(2):74.<br />J Pediatr. 2009;154(6):888.<br />
24. Median age of first <br />symptom was 19 yr<br />Median age at CVID diagnosis was 33.9 yr<br />
25. Delay between first symptom <br />and diagnosis of CVID<br />
30. 73%: RS infection<br />
31. Coincidence of granulomatous disease and <br />autoimmmune cytopenia with splenomegaly in CVID<br />
33. Mary Lucas et al. JACI 2010<br />
36. Pulmonary manifestations <br /><ul><li>73 % of CVID develop chronic structural pulmonary complications: bronchiectasis and bronchial wall thickening</li></ul> Pediatr Allergy Immunol. 2010;21(5):793.<br /><ul><li>54 children with CVID, structural lung disease was found in >85 %of patients
37. Chest. 2010;138(2):371. </li></li></ul><li>Pulmonary manifestations<br /><ul><li>Obstructive flow-volume curves found in 50 - 94 % of pts.</li></ul> Pediatr Allergy Immunol. 2010;21(5):793.<br /><ul><li>12 CVID, 83 %asthma, none life-threatening symptoms.
38. Ann Allergy Asthma Immunol. 2006;97(5):653
39. Obstructive lung disease in children with CVID appears to be higher than adults. </li></li></ul><li>
40. Allergic diseases<br /><ul><li>38 %of ptsin one of cohorts had some evidence of an allergic disease:food allergy, eczema, urticaria, rhinitis, asthma.
41. J Pediatr. 2009;154(6):888.
42. 83 % had asthma.
43. Ann Allergy Asthma Immunol. 2006;97(5):653</li></li></ul><li>
46. Gastrointestinal problems <br /><ul><li>Diarrhea, malabsorption, wtloss are common problems in CVID.
47. ClinImmunol. 1999;92(1):34.
48. GI infections: H. pylori and Giardia lamblia. Salmonella, Shigella, Campylobacter.
49. Ann Intern Med. 1993;118(9):720
50. Crohn's disease and ulcerative colitis
51. ClinImmunol. 1999;92(1):34.
52. Nodular intestinal hyperplasia occurs relatively frequently in adolescents with CVID
61. Malignancy<br /><ul><li>Lifetime risk of malignancy: 1.4 - 7 %
62. The most frequently diagnosed disorder is B cell lymphoma </li></ul>Am J Hematol. 2002;69(3):171.<br />
64. Neurodegenerative diseases or encephalopathy <br /><ul><li>adults with CVID, enteroviral and JC virus infection can cause neurodegeneration.
65. Enteroviralinfection has not described in pediatric CVID.
66. In contrast, neurodegenerative diseases described in other pediatric immunodeficiencies (esp. X-linked agammaglobulinemia)</li></ul>Brain. 1996;119 ( Pt 1):1.<br />Ann Allergy Asthma Immunol. 2007;98(5):483<br />
67. BAFF-R<br />TACI<br />
69. ICOS DeficiencyICOS Deficiency<br /><ul><li>2% of patients with CVID
70. Autosomal recessive trait
71. Serum IgG and IgA levels were markedly reduced in all patients
72. IgG<1.9-2.55 g/L
74. Serum IgMlevel
75. reduced in 6/9 patients
76. low normal values in 3/9 patients</li></ul>C.Bacchellietal.ClinicalandExperimentalImmunology2007, 149:401–409.<br />Yongetal.ImmunologicalReviews2009;229:101–113.Park MA et al. Lancet 2008;372:489-502<br />
79. TACI mutation<br /><ul><li>10-20% of CVID patients
80. Associated with
83. Tonsillar hyperplasia
84. follicular nodular hyperplasia of GI
86. hemolytic anaemia
87. Autoimmune thrombocytopaenia
88. thyroiditis</li></ul>TACI MutationTACI MutationPark MA et al. Lancet 2008;372:489-502.<br />Young PFK et al. ImmunolAllergy ClinN Am 2008;28:367-86.<br />C.Bacchellietal.ClinicalandExperimentalImmunology2007;149:401–409.<br />
89. BAFF-R Deficiency<br /><ul><li>Described in only 1 patient
90. 60-year-old male with hypogammaglobulinaemia
91. Profound reduction of both class switch (CD27+, IgM-, IgD-) and non-switched memory (CD27+, IgM+, IgD+) Transitional B cell (CD38+++, IgM++) Plasmablasts(CD38+++, IgM-)</li></ul>Park MA et al. Lancet 2008;372:489-502.<br />C.Bacchellietal.ClinicalandExperimentalImmunology2007;149:401–409.<br />
92. Muts5(MSH5)<br /><ul><li>A gene encoded in MHC classIII region
93. A critical role in regulating meiotic homologous recombination
94. A role in class switch recombination
95. Msh5 Mutation: associated with CVID and selective IgA deficiency</li></li></ul><li>
98. MANAGEMENT<br />
99. Immune globulin<br /><ul><li>IgGreplacement therapy started early, cycle of recurrent infections leading to progressive lung damage can be mitigated.
100. Non-infectious complications of CVID, such as autoimmune cytopeniasprevented or treated by immune globulin therapy</li></li></ul><li>Immune globulin<br /><ul><li>Igshould not be given until evaluation of patient's immune system including specific antibody responses.
101. Plans should be made to discontinue infusions for at least 4mo, in order to reassess patient’s current immune status. </li></li></ul><li>
105. Evaluation of illnesses<br /><ul><li>Children generally have higher rate of viral infection than adults, due to increased exposure and other factors
106. CVID and fever should be evaluated promptly. identify organisms such as rapid viral identification kits for influenza or RSV.
107. Choice of ATB on culture data and test results and using narrow-spectrum drugs, avoid bacterial resistance. </li></li></ul><li>Monitoring pulmonary status<br /><ul><li>Monitoring child for progressive but subclinical pulmonary damage is important since ptscan develop chronic pulmonary disease.
108. HRCT of chest may be of value in detecting early and progressive pulmonary structural damage
109. Repeat exams for decision such as administration of ATB or immune suppressants or increase in dose of Ig.</li></li></ul><li>Vaccination<br /><ul><li>Live viral vaccines contraindicated in CVID.
110. Killed viral and bacterial vaccines: hope that generate T cell-mediated immune responses that may afford some additional protection beyond that obtained with Igreplacement therapy.
111. Many children will retain ability to mount responses to some polysaccharide Ag, while they are non-responsive to others.
112. Immunization against transmissible infectious agents is encouraged for close family members.
113. Passive protection with hyperimmune globulin preparations, such as tetanus and varicella, is usually not necessary in patients already receiving standard Igreplacement therapy.</li></li></ul><li>PROGNOSIS<br /><ul><li>Life span of children with CVID has been significantly lengthened since Ig replacement therapy became standard of care
114. Prognosis is good.
115. Death during childhood from complications of CVID is extremely rare once immune globulin therapy is instituted.
116. Those children diagnosed after irreversible pulmonary disease has developed may have shorter life span</li></li></ul><li>