Common variable immunodeficiency 2017
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Common variable immunodeficiency 2017 Presented by Jintana Chataroopwijit, MD. June30, 2017
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Common variable immunodeficiency 2017
- 1. Common Variable Immune Deficiency Jintana Chataroopwijit, MD. 30 June 2017
- 2. Introduction Common variable immunodeficiency (CVID) First, defined in 1971 by WHO separate less well- defined antibody deficiency syndromes from others with a more coherent clinical description and Mendelian inheritance Most common and clinically most important severe primary antibody deficiency Heterogenous disease
- 3. Consensus definition of CVID (ICON2016) 1. Most patients : > 1 of clinical manifestations (infection, autoimmunity, lymphoproliferation) with fulfill criteria 2-5 2. Hypogammaglobulinemia (The IgG level must be repeatedly low in at least 2 measurements more than 3 weeks apart), exception IgG <300 mg/dl) 3. IgA or IgM level must also be low
- 4. Consensus definition of CVID (ICON2016) 4. Impairment of response to at least 1 type of antigen (T dependent or T independent) esp. IgG > 100 mg/dl 5. Other causes of hypogammaglobulinemia must be excluded
- 5. Cause of Hypogammaglobulinemia Arthritis Research and Therapy 2012, 14:223
- 6. Cause of Hypogammaglobulinemia Arthritis Research and Therapy 2012, 14:223
- 7. Consensus definition of CVID (ICON2016) 6. Genetic studies to investigate monogenic forms of CVID or for disease-modifying polymorphisms are not generally required for diagnosis and management in most of the patients, especially those who present with infections only without immune dysregulation, autoimmunity, malignancy, or other complications single gene defects may be amenable to specific therapies (eg, stem cell therapy) and molecular genetic diagnosis should be considered when possible
- 8. Epidemiology Prevalence : no precision 1:25,000- 1:200,000 Male = Female Age of onset bimodal distribution (peak 1st & 3rd decade) Significant delay between the onset of symptoms and the establishment of the diagnosis ICON 2016
- 9. Age at onset of symptoms and diagnosis J Allergy Clin Immunol 2014; 134: 116-26
- 10. Pathogenesis Loss of B cell function T and B cell dysregulation defective antibody production
- 11. B cell development Common variable Immunodeficiency (CVID) Eur J Pediatr 2011;170:693-702.
- 12. Park MA.,et.al.Lancet 2008; 372: 489–502 APRIL-BAFF network Kopecký O, Int. J. Immunogenet (2007) • Mutation in TNFRSF13B or TACI occur 10% of CVID • Autosomal dominant • Increase risk of lymphoproliferation and autoimmunity
- 13. Park MA.,et.al.Lancet 2008; 372: 489–502 The inducible costimulator gene (ICOS) • Mutation in ICOS occur 2% of CVID • Autosomal recessive
- 14. The B Cell receptor signaling complex Park MA.,et.al.Lancet 2008; 372: 489–502
- 15. Genetic defect in CVID Park MA, et al. Lancet 2008; 372: 489–502 90% unknown genetic defect
- 16. B cell signaling molecule
- 17. Liadaki K.,New facets of antibody deficiencies, CurOp in Immu,2013
- 20. Classification schemes defining subgroups of patients with CVID on the basis of flow cytometric B-cell immunophenotyping ICON 2016
- 21. Clinical phenotypes in CVID Jolles. J ALLERGY CLIN IMMUNOL PRACT, NOVEMBER/DECEMBER 2013
- 22. Frequency of clinical feature in cohort (n=902) J Allergy Clin Immunol 2014; 134: 116-26
- 23. Infectious complications in CVID •Sinusitis is the commonnest clinical presentation in children followed by otitis media and pneumonia •Encapsulated (H. influenzae, Streptococcus pneumoniae) or atypical (Mycoplasma spp.) bacteria Arthritis Res Ther 2012;14:223-233.
- 24. Infection in CVID Respiratory : upper and lower Gastrointestinal Genitourinary tracts : Ureaplasma urealyticum Arthritis : Ureaplasma or Mycoplasma organisms Paediatric Respiratory Reviews 19 (2016) 56–6 ICON 20161
- 25. • The most severe disease in the middle lobe and some involvement of the lower lobes • Airway wall thickening and tree-in-bud pattern Touw CML, et al. Pediatr Allergy Immunol 2010: 21: 793–805. Paediatric Respiratory review 2016: 19 : 56-61 CVID: Clinical phenotype • Bronchiectasis (10-20%)
- 26. Radiology finding in primary antibody deficiency ALLERGY CLIN IMMUNOL PRACT NOVEMBER/DECEMBER 2016
- 27. CVID: Clinical phenotype Autoimmune diseases (20% ) Resnick ES.,et.al. Blood. 2012;119(7):1650-1657
- 28. CVID: Clinical phenotype Gastrointestinal complications (20-25%) Resnick ES.,et.al. Blood. 2012;119(7):1650-1657 Correlated with : autoimmunity, splenectomy, lobectomy, low IgM level, age of onset Arthritis Research and Therapy 2012, 14:223 ICON 2016
- 29. CVID: Clinical phenotype Granulomatous lesions (10–22%) Multisystem granulomas : increase morbidity and mortality in patients with CVID Mean age at onset is 18–34 years, most common in adults Histology : non-caseating granulomas The prevalence of autoimmunity (AIHA) is higher (>50%) in patients with CVID and granulomatous disease than in those without (47%) Park MA,et.al. Lancet 2008; 372: 489–502
- 30. Resnick ES.,et.al. Blood. 2012;119(7):1650-1657 • Granulomatous lesions CVID: Clinical phenotype
- 31. CVID: Clinical phenotype Neoplasia : 6% to 9% Patients with CVID have a high risk of neoplastic disease The most common malignancies were non-Hodgkin lymphoma and gastric cancers Accurate clinical and family histories of neoplasia along with consideration of surveillance for malignancy in patients with CVID Park MA,et.al. Lancet 2008; 372: 489–502 J Allergy Clin Immunol Pract. 2016
- 32. Summary : Infections and autoimmune and/or inflammatory complications in CVID
- 33. Jolles. J ALLERGY CLIN IMMUNOL PRACT, NOVEMBER/DECEMBER 2013
- 34. Approach to CVID History Recurrent infection/Autoimmunity Exclude 2° Hypogammaglobulinemia Other conditions : Allergy, Daycare, Sibling, CF, primary ciliary dyskinesia, FB, passive smoker, GERD, anatomical defects DDx : XLA, AR agammaglobulinemia, HGIM, THI, SAD, SIGAD, XLP
- 35. Immunological work up B-cell RESULT • Number Normal (except : ICOS, BAFF-R) • Serum IgG,A,M,E • Low IgG : most < 400 mg/dL • IgA or IgM level must also be low • Isohemagglutinin • Specific antibody production (TI and TD) • Impairment of response to at least 1 type of antigen (TD or TI) • performed esp. IgG > 100 mg/dl)
- 36. Immunological work up T-cell RESULT • Number Normal • Function Variable 50% Abnormal • Absent DTH to recall antigens • Depressed responses to mitogens or specific antigens Genetic • TACI (TNFRSF 13B) 10-20% (AD) • ICOS 2% (AR) • BAFF-R (TNFRSF 13C) <1% (AR) • CD19 1% (AR)
- 37. Treatment 1. Immunoglobulin replacement therapy 2. Immunization 3. Treatment of complications 4. Special considerations
- 38. Immunoglobulin replacement therapy Dose : 400 to 500 g/kg/month (IVIG and SCIG) Preexisting bronchiectasis: 600 mg/kg/month Enteropathy or splenomegaly: 600 – 800 mg/kg/month ICON 2016
- 39. Health outcomes in correlation to IgG trough levels J Allergy Clin Immunol 2014; 134: 116-26
- 40. CVID: Vaccinations J Allergy Clin Immunol 2016; 4:1066-75 • A : No possibility of harm, benefit possible, administration recommended, use according to routine schedule • B : no possibility of harm, benefit unlikely, administration NOT recommended • C : possibility of harm (significant), benefit unlikely, administration NOT recommended • D : possibility of harm (small), benefit likely, administration recommended
- 41. CVID: Vaccinations • Avoid all live-attenuated vaccines • Only inactivated or subunit vaccine should be given • Consider yearly influenza vaccine • C : possibility of harm (significant), benefit unlikely, administration NOT recommended • D : possibility of harm (small), benefit likely, administration recommended J Allergy Clin Immunol 2016; 4:1066-75 ICON 2016
- 42. Summary vaccination in CVID J Allergy Clin Immunol 2016; 4:1066-75
- 43. Treatment of complications Rhinosinusitis Bronchiectasis • Saline nasal rise : mucus clearance • >3 breakthrough infections of extremely severe infection on IgG Antibiotic prophylaxis ex. Amoxicillin, Azithromycin, SMX/TMP Autoimmune cytopenias • Prednisolone 1-2 mg/kg daily • IVIG : 1-2 g/kg/month • Antirhesus antigen globulin • Rituximab for recurrent ITP and/or AIHA • Splenectomy Granulomatous disease • Corticosteroids (low doses for long periods) • Steroid sparing agent/ Immunosuppressive ICON 2016
- 44. Enteropathy • 5- aminosalicylic acid • Budesonide • Prednisolone / immunosuppressive • Infliximab severe enteropathy • Bacterial overgrowth may be ameliorated by broad-spectrum antibiotics • Treat deficiency of fat-soluble vitamins Interstitial lung disease • High mortality • All patients should have at least 1 HRCT scan at diagnosis • azathioprine and rituximab granulomatous/lymphocytic infiltrates • Corticosteroids + cyclosporine prominent T cell infiltrate • Anti-TNF antibody complex interstitial lung disease Treatment of complications ICON 2016
- 45. Lymphoproliferation persistent hypertrophy of lymph nodes lymphoma or autoimmune lymphoproliferative syndrome : Rx Corticosteroid An acute increase in adenopathy or splenomegaly possible malignant transformation. Lymphoma • Protocol Stem cell therapy The indication for HSCT • Hematologic malignancy : Lymphoma • Had 1 or more of the following conditions refractory to conventional therapies: autoimmune cytopenias, respiratory or gastrointestinal infections, interstitial/granulomatous lung disease, and/or autoimmune enteropathy Treatment of complications ICON 2016
- 46. Suggested monitoring for patients with CVID
- 47. CVID: Surveillance Lifetime surveillance for cancer and autoimmunity no standardized specific recommendations for routine or scheduled testing or imaging Routine monitoring studies related to IgG replacement ( CBC, LFT, BUN, Cr: minimal of q 6-12 months) For those patients who remain healthy on replacement immunoglobulin At a minimum, age-appropriate cancer screening as the general healthy population Colonoscopy, prostate examination, pap smears, mammograms Park MA,et.al. Lancet 2008; 372: 489–502 Francisco A, et al. Practice parameter, JACI 2015
- 48. Initial and follow up Arthritis Research and Therapy 2012, 14:223
- 49. CVID: Prognosis Life expectancy of CVID: 12 years -> 50 years Reduced survival: age at diagnosis, lower baseline IgG, higher IgM and fewer peripheral B cells Risk of death: 11 times higher for patients with non- infectious complication (lymphoma, chronic hepatits, structural lung disease, chronic gastrointestinal disease) Arthritis Res Ther 2012;14:223-233.
- 50. Clinical phenotype in 2 age group J Allergy Clin Immunol, November 2012
- 51. Association of clinical and laboratory finding with survival J Allergy Clin Immunol, November 2012
- 52. Thank you for your attention
Hinweis der Redaktion
- เริ่มพูดถึงครั้งแรกในWHOตั้งแต่ปี 1971 แต่ไม่ได้มีการdefineชัดเจน ให้เป็นกลุ่ม antibody deficiency ที่ไม่ได้เข้ากับกลุ่มใดๆ แต่มีอาการแสดงคล้ายๆกันในกลุ่ม และมีการถ่ายทอดกันทางพันธุกรรม และถือเป็นโรคที่พบมากที่สุดในกลุ่มprimary antibody deficiency แต่patternโรคนั้นมีความหลากหลายกันภายในกลุ่ม
- ล่าสุดมีการอัพเดตdefinitionของโรคนี้ใหม่โดย international consensus document ตีพิมพ์ใน journal pf allergy and clinical immunology in practice 2016 คือ ต้องมีอาการแสดงของโครนี้ ซึ่งปะกอบด้วย การติดเชื้อซ้ำซ้อน autoimmunity หรือ lymphoproliferation ร่วมกับ crteria 2-5 คือ Hypogammaglobulinemia ดู IgG level ต่ำกว่า 2SD ของค่าปกติตามอายุ โดยมีการเจาะซ้ำสองครั้งที่ห่างกันอย่างน้อยสามสัปดาห์ ยกเว้น กรณีที่เจาะแล้ว level IgG น้อยกว่า 300 ส่วนIgAหรือ IgM ต้องต่ำอย่างน้อยตัวใดตัวหนึ่ง
- Impaired antibody response ต่อ antigen อาจเป็น T depentหรือ independentก้อได้ โดยเฉพาะในคนไข้ที่ค่า IgG มากกว่า 100 และต้องไม่มี สาเหตุอื่นๆ ที่ทำให้เกิด hypogam
- ในส่วนของ genetic investigation ไม่จำเป็นต้องทำในคนไข้ทุกคน ยกเว้นในกรณีที่ส่งสัยเป็นกลุ่ม single gene defect อาจพิจารณาส่งตรวจเพื่อประโยชน์ในการพิจารณาการรักษา เช่น stem cell therapy เป็นต้น ถ้าสามารถส่งตรวจได้
- Prevalenceมีความvaryกันมาก ขึ้นกับgenetic ภูมิประเทศ วิธีการตรวจ definition awarenessของแพทย์และคนไข้ rangeตั้งแต่1:10000ถึง1:200000 โดยพบทั้งชายและหญิงใกล้เคียงกัน ageที่พบแบ่งเป็ง2ช่วงคือ 10ขวบปีแรก และ วัยกลางคนช่วง30ปี ส่วนonset of symptom and onset of diagnosis กัอจะแตกต่างกันขึ้นกับข้างต้น
- Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively. 33.7% patients had an onset before the age of 10 years : very pronounced peak. Male 39.8% and female 27.9% 2 peaks of diagnosis during childhood and the other between 30 and 40 years of age median diagnostic delay varied considerably between countries : all median diagnostic delay was 4.1 years
- Mature B cell ไม่เปลี่ยนเป็น Plasma cell
- B cells originate from lymphoid precursors in the bone marrow ซึ่งเป็นที่ repertoire of B cells จำนวนมากและมี B cell receptors (BCRs) ต่างๆ เกิดขึ้น ประกอบไปด้วย signaling complex และ membrane bound IgM molecule โดยที่ b cell receptor จะสามารถ recognize antigen ต่างๆ หลังจากออกจาก bone marrow : IgM positive B cells can be activated by antigen and enter a germinal center in lymphoid tissue germinal center in lymphoid tissue จะเป็นบริเวณที่เกิด T cell-dependent antibody response เกิด การสร้าง IgG, IgA, and IgE positive plasma cells และ memory B cells จากการเริ่มขบวนการ class switch recombination (CSR) Somatic hypermutation (SHM) ที่ region ต่างๆ ของ Ig heavy and Ig light chainsทำให้เพิ่ม affinity ของ BCR กับ antigen affinity maturation Antigen(Ag)-independent B cell differentiation occurs in the bone marrow ส่วน Ag-dependent B cell differentiation occurs in the periphery หลังจากที่โดน activate by antigen, B cells develop in a T cell-dependent way in the germinal center and in a T cell-independent ในส่วนของ the marginal zone of the spleen Defects of survival, Ag stimulation, B–T interaction, TI response, CSR/SHM can result in PAD Memory B cells are able to rapidly differentiate in new plasma cells in case of reinfections การผลิต antibodies ต่อ polysaccharide antigens ของ encapsulated bacteria เช่น pneumococci and meningococci, ต้องใช้ second T cell-independent B cell response ที่ marginal zone of the spleen ส่วน T cell-independent B cell response นี้จะยัง immature ในเด็กที่อายุน้อยกว่า 2 ปี low number of switched memory B cells in the peripheral blood is associated with autoimmunity, granulomas, and respiratory infection
- Both APRIL and BAFF molecules bind two type III membrane receptors, BCMA, TACI (Schneider et al., 1999) ทั้งสองตัวอยู่ใน superfamily of TNF receptors และตัวที่สามคือ BAFFR belonging to the TNF-R family BCMA is expressed exclusively on B lymphocytes TACI or TNFRSF13B: TNF receptor superfamily 13B encoding transmembrane activator - expressed both on B lymphocytes and activated T lymphocytes. TACI induces nuclear factor κB activation and regulates class-switching of immunoglobulins and the antibody response to T-independent antigens BAFF-R : unique receptor for BAFF (Bodmer et al., 2002; Losi et al., 2005). This membrane molecule is predominantly expressed on B lymphocytes and only on part of activated T lymphocytes (Schneider & Tschopp, 2003; Martin & Vishva, 2005) BAFF-R interactions provide crucial survival signals for differentiation of peripheral B cells Interactions of APRIL and BAFF, expressed on monocytes and macrophages, with their receptors on B lymphocytes are evidence of the significance of natural immunity for the correct antibody response (McHeyzer-Williams, 2003; de Durana et al., 2006) Absence of any of the previously mentioned signals defect of terminal differentiation of a mature B lymphocyte into plasmatic and memory cells, which are manifested by antibody immunodeficiency (Salzer & Grimbacher, 2005) (Figure 2) TACI and BAFF-R ligands are expressed on macrophages, monocytes, and dendritic cells. BAFF-R and TACI are cell-surface receptors belonging to the TNF-receptor family that play a part in B-cell differentiation and function. BAFF–BAFF-R interactions provide critical survival signals for differentiation of peripheral B cells. The role of BAFF-TACI interactions is less clearly defined. TACI signals intracellularly through the TNF receptor-associated factors (TRAF) to induce nuclear factor-κ-B activation. TACI also interacts intracellularly with calcium modulator and cyclophilin ligand (CAML). Through interaction with APRIL, TACI regulates isotype class switching of immunoglobulins and the antibody response to T-independent antigens. TACI (tumor necrosis factor receptor superfamily, member 13b) เป็น transmembrane protein ที่ ควบคุม T cell-independent B cell antibody responses, isotype switching, and B cell homeostasis BAFFR (B cell-activating factor receptor): one of three known receptors for BAFF, a critical regulator of B-cell and T-cell function
- ICOS (Inducible t-cell co-stimulator) เป็น CD28-superfamily costimulatory molecule that enables T-cell interactions with B cells, monocytes, and dendritic cells. ICOS is upregulated on both CD4 and CD8 effector and memory T cell and activated natural-killer cells, and it enhances natural-killer-cell function. ICOS is expressed constitutively in germinal centres and T-cell zones of spleen, lymph nodes, and Peyer’s patches. The first reported genetic defect associated with CVID and characterised by a deficiency of ICOS, which is expressed on activated T cell, identified in nine individuals with CVID from four apparently unrelated families. presented with recurrent bacterial infections, splenomegaly, autoimmune neutropenia, intestinal lymphoid hyperplasia, and neoplasia. ICOS-deficient patients have few peripheral B cells, few or no class-switched memory B cells, and hypogammaglobulinemia. T cells produce very little interleukin 10, which may be associated with the defective formation of germinal centres leading to impaired B-cell memory (figure 4). autosomal- recessive trait
- CD19 and CD81 เป็น transmembrane proteins ทำหน้าที่ amplify signal ผ่าน B cell receptor protein CD20 เป็น activated-glycosylated expressed ที่ surface of B-cells CD19 is a B-cell-specific cell-surface marker that is part of the B-cell coreceptor along with CD21 and CD81. CD19 is expressed throughout B-cell maturation from pro-B cells through to plasmablasts, before CD21 or CD81, it is not expressed on plasma cells. In patients with this defect, the total number of B cells (CD20+) in blood is normal with low or undetectable surface expression of CD19 , and the numbers of CD27+ memory B cells and CD5+ B cells are decreased (figure 4). CD19 knockout mice have deficient antibody responses to most antigens. CD19 is expressed on B cells from an early stage of development and therefore seems to play a part in signalling through the B-cell receptor even without forming a complex with CD21 and CD81.
- Overview of B cell signaling molecules involved in antibody deficiency in humans วงกลมสีแดง เป็น gene ตัวใหม่ Highlighted with red are the novel genes ที่ทำให้เกิด โรค CVID ส่วนในกล่องสีฟ้า คือตัวที่เดยกล่าวไปแล้ว ประกอบด้วย ICOS,…… CD27 (TNFRSF7) เป็น TNF receptor family member, interacts with CD70 ซึ่งจะมีผลต่อ function of T-cells, B-cells and NK-cells โดย CD27 ได้เป็น marker for memory B cells มี report CVID น JACI 2012 โดย van Montfrans พบ homozygous mutation (c.24G>A, p.Trp8*) ของ CD27 gene ในพี่น้องน้อง 2 8oที่ครอบครัวมีประวัติ consanguineous ทำให้เกิด absent CD27 expression, hypogammaglobulinemia and persistent EBV infection และมี report โดย Salzer ใน hematologica 2013 พบ another homozygous CD27 defect (c.158G>A, p.Cys53Tyr) ในคนไข้ 8 คน จาก 3 ตรอบครัว ที่ พบ life-threatening EBV-lymphoproliferative disease and hypogammaglobulinemia แต่อย่างไรก็ตาม ยังไม่สามารถ confirm ได้ว่า สาเหตุเกืดจาก loss of CD27 function alone, or secondary to the EBV infections ปี 2013 mutation in the TNFSF12 gene : TNF-related weak inducer of apoptosis (TWEAK) ในส่วนของ TNF-homology domain (THD) of TWEAK (c.433C>T, p.Arg145Cys) ในคนไข้ มีประวัติ recurrent infections, reduced IgM and IgA serum level and impaired antibody responses to both protein and polysaccharide vaccines. This mutation associates with BAFF and may dominantly inhibit B-cell survival and proliferation as well as CSR through downregulation of the noncanonical BAFF- induced NF-kB pathway เกี่ยวกับNK cells พบรายงานคนไข้มี severe cutaneous papilloma infection CD21 deficiency ได้ report โดย Thiel et al. ใน JACI 2012 เป็น 28-year-old male with hypogammaglobulinemia, recurrent respiratory tract infections and a reduced response to pneumococcal polysaccharide vaccination โดยลักษณะ mutation เป็น compound heterozygous mutations identified in the CD21 gene (c.1225+1G>C, c.2297G>A) absence of CD21 expression นอกจากนี้ clinical phenotype ไม่รุนแรงเท่ากับ CD19-deficient and CD81-deficient น่าจะเกิดจาก deficiencyของ2ตัวนี้จะลด expression of other co-receptors PLCG2 gene mutation แบบ deletion ทำให้เกิด complex phenotype of cold-induced urticaria with antibody deficiency and autoimmunity รายงาน ปี 2012 โดย Ombrello et cause a gain of phospholipase Cg2 (PLCg2) function, which leads to production of proteins with constitutive phospholipase activity but a reduced PLCg2-dependent intracellular signaling at a physiological temperature. B cells and mast cells expressing the mutant form of PLCg2 had enhanced cell signaling and cellular activation at subphysiological temperatures, which may explain the characteristic cold-induced skin rash and inflammation. Another gain-of-function mutation in PLCG2 (c.2120C>A, p.Ser707Tyr) 2 patients with dominantly inherited autoinflammatory disease, mild antibody deficiency but notably, no cold temperature-induced symptoms [39]. The mutation resulted in an opposite effect as compared to the large deletions, with increased cellular signaling at physiological temperature, which might explain the distinct autoinflammatory phenotype observed in these two patients [39]. almost total absence of circulating, class-switched memory B cells, despite the divergent functional effects of these mutants.
- low cytometric phenotyping and measurement of kappa-deleting recombination excision circles (KRECs) distinguished 5 possible subgroups or defects: 1) B-cell production 2) early peripheral B-cell maturation or survival 3) B-cell activation and proliferation 4) germinal center 5) postgerminal center. some patients, calcium flux after activation of the B-cell receptor may be impaired (note that these correspond to low switched memory B cells) with expansion of the CD21low population
- 1. No other disease-related complications (infections only) 2. Cytopenias (thrombocytopenia, autoimmune hemolytic anemia, and/or neutropenia) 3. Polyclonal lymphoproliferation (granuloma, lymphocytic interstitial pneumonia, persistent unexplained lymphadenopathy) 4. Unexplained enteropathy one or more noninfectious complications is associated with an almost 11-fold increase in mortality during follow-up. Patients with no other disease-related complications had a long-term survival of 95% versus 42% in those with noninfectious complications
- Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively. total frequency of the clinical features in 902 patients with available data
- Radiologic findings of lung disease in PAD. A, Bronchiectasis (marked by white arrows) in a patient with CVID. B, A patient with CVID with bilateral pulmonary nodules and mediastinal lymphadenopathy. C, A patient with CVID with innumerable nodular opacities, bronchiectasis, and mediastinal lymphadenopathy. D, Patient with IgA/IgG2 deficiency (IgA, <10 mg/dL; IgG, 997 mg/dL; IgG2, <16 mg/dL) demonstrating multiple noncalcified lung nodules.
- Autoimmune thrombocytopenic purpura and autoimmune hemolytic anaemia are the most common occurring in 5–8% of CVID patients Splenomegaly anti-IgA antibodies, pernicious anemia and autoimmune thyroiditis Rheumatoid arthritis, vitiligo, vasculitis(less common )
- Up to 50% of patients with CVID have chronic diarrhea with malabsorption Other : Crohn’s disease, intestinal granulomatous disease, intestinal parasitic bacterial or viral infections, celiac sprue, intestinal lymphangiectasia
- FIGURE 2. Infections and autoimmune and/or inflammatory complications in CVID. The predominant organisms and sites of infection are shown on the left, with the inflammatory and autoimmune complications on the right. Other autoimmune complications include neutropenia, vitiligo, Sjögren syndrome/Sicca syndrome, autoimmune thyroiditis, diabetes mellitus, multiple sclerosis, pernicious anemia, systemic lupus erythematosus, antiphospholipid syndrome, uveitis, juvenile rheumatoid arthritis, lichen planus, vasculitis, and psoriasis. 106 (Drawn by Pippa Jolles.) LIP, Lymphocytic interstitial pneumonia; GLILD, granulomatous lymphocytic interstitial lung disease.
- Higher rates of respiratory infection and poorer outcomes are associated with underdosing IgG and vice versa Adverse events tend to be associated with rapid infusion rates, concurrent acute infections, and previously untreated patients, when a significant time has elapsed between infusions (>6 weeks), or when there is a change in product SCIG doses in adults vary from 100 to 200 mg/kg/week and dosing intervals from daily to twice weekly, once a week, or every 2 weeks. Absorption of IgG administered subcutaneously takes 3 to 7 days. Some practitioners prefer to initiate therapy with IVIG until the patient is stable and then transition to SCIG, whereas others initiate SCIG directly
- Analyzed data on 2212 patients with a confirmed diagnosis of CVID reported in the ESID Database. CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively. Health outcomes in correlation to IgG trough levels. In summary, we found that the differences in days in the hospital and serious bacterial infections between the groups at less than and greater than 4 g/L was higher than the differences using the other cutoffs. This is valid, irrespective of the route of administration. Of the 11 clinical features used in the previous analysis, only pneumonia showed a correlation with serious infections, and bronchiectasis showed a correlation with missed days. When we further analyzed these, there was a significant difference in outcome between IgG groups for patients without pneumonia, with the number of serious infections slightly decreasing with increased IgG levels. However, there were no differences for patients with pneumonia. In contrast, a decrease in the number of missed days only existed in patients with bronchiectasis but not in those without. B : Patients hospitalized because of immunodeficiency Because the total number of serious infections and days in the hospital were low, the graph shows the percentage of affected patients.
- Granulomatous disease. Treatment of granulomas is empirical.78,231,232 Corticosteroids, in low doses for long periods to avoid steroid-related complications, have been found to result in short-term resolution in sites that are easily monitored by endoscopy or imaging. Steroid-sparing agents, such as azathioprine, cyclosporine, or other agents, have been tried with varying success. Infliximab has been successful for skin granulomas, but caution is advised in view of the increased risk of pyogenic or mycobacterial infections.
- Granulomatous disease. Treatment of granulomas is empirical.78,231,232 Corticosteroids, in low doses for long periods to avoid steroid-related complications, have been found to result in short-term resolution in sites that are easily monitored by endoscopy or imaging. Steroid-sparing agents, such as azathioprine, cyclosporine, or other agents, have been tried with varying success. Infliximab has been successful for skin granulomas, but caution is advised in view of the increased risk of pyogenic or mycobacterial infections.
- Granulomatous disease. Treatment of granulomas is empirical.78,231,232 Corticosteroids, in low doses for long periods to avoid steroid-related complications, have been found to result in short-term resolution in sites that are easily monitored by endoscopy or imaging. Steroid-sparing agents, such as azathioprine, cyclosporine, or other agents, have been tried with varying success. Infliximab has been successful for skin granulomas, but caution is advised in view of the increased risk of pyogenic or mycobacterial infections.
- JACI 2012, By using data on clinical complications and disease progression from 334 patients with CVID from 7 European centers including Oxford (‘‘Northern European cohort’’ To examine the question of the poorer prognosis in children with a diagnosis of CVID before their 16th birthday, clinical phenotypes were compared in patients younger than 16 years with those older than 16 years Table E2 show that there were more cytopenic phenotypes in the younger group; the distribution of the other clinical phenotypes was similar.
- Clinical and laboratory findings for survival. Given the different prognoses for the clinical phenotypes in the original data,E1 this was reexamined with the revised criteria by using the combined cohorts. Table E5 shows the results.