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• W2024897191 abstract "Common variable immunodeficiency (CVID) is the most common and clinically most important severe primary antibody deficiency and is characterized by low levels of IgG, IgA, and/or IgM, with a failure to produce specific antibodies. This diagnostic category represents a heterogeneous group of disorders, which present not only with acute and chronic infections but also with a range of inflammatory and autoimmune disorders as well as an increased incidence of lymphoma and other malignancies. Patients can now be categorized into distinct clinical phenotypes based on analysis of large cohort studies and be further stratified by immunologic laboratory testing. The biologic importance of this categorization is made clear by the 11-fold increase in mortality if even one of these phenotypes (cytopenias, lymphoproliferation, or enteropathy) is present. Limited progress in defining the underlying molecular causes has been made with known causative single gene defects accounting for only 3% of cases, and, for this and the reasons mentioned above, CVID remains resolute in its variability. This review provides a practical approach to risk stratification of these complex phenotypes by using current clinical categories and laboratory biomarkers. The effects of infection as well as inflammatory and autoimmune complications on different organ systems are discussed alongside strategies to reduce diagnostic delay. Recent developments in diagnostics and therapy are also explored. Common variable immunodeficiency (CVID) is the most common and clinically most important severe primary antibody deficiency and is characterized by low levels of IgG, IgA, and/or IgM, with a failure to produce specific antibodies. This diagnostic category represents a heterogeneous group of disorders, which present not only with acute and chronic infections but also with a range of inflammatory and autoimmune disorders as well as an increased incidence of lymphoma and other malignancies. Patients can now be categorized into distinct clinical phenotypes based on analysis of large cohort studies and be further stratified by immunologic laboratory testing. The biologic importance of this categorization is made clear by the 11-fold increase in mortality if even one of these phenotypes (cytopenias, lymphoproliferation, or enteropathy) is present. Limited progress in defining the underlying molecular causes has been made with known causative single gene defects accounting for only 3% of cases, and, for this and the reasons mentioned above, CVID remains resolute in its variability. This review provides a practical approach to risk stratification of these complex phenotypes by using current clinical categories and laboratory biomarkers. The effects of infection as well as inflammatory and autoimmune complications on different organ systems are discussed alongside strategies to reduce diagnostic delay. Recent developments in diagnostics and therapy are also explored. INFORMATION FOR CATEGORY 1 CME CREDITCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The accompanying tests may only be submitted online at www.jaci-inpractice.org/. Fax or other copies will not be accepted.Date of Original Release: November 2013. Credit may be obtained for these courses until December 31, 2014.Copyright Statement: Copyright 2012-2014. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic and immunologic disease to those who research, treat, or manage these disorders.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Stephen Jolles, FRCP, FRCPath, PhDActivity Objectives1.To understand the genes currently known to cause a common variable immunodeficiency (CVID) phenotype.2.To understand the clinical phenotypes of CVID.3.To understand the available biomarkers that may aid risk stratification in CVID.4.To understand advances in imaging and treatment of chest disease in CVID.Recognition of Commercial Support: None to report.Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: S. Jolles is on advisory boards for CSL Behring, Baxter, BPL, Biotest, and Octapharma; has received consultancy fees from BPL; has received research support from CSL Behring and Baxter; and has received lecture fees from CSL Behring, Baxter, Biotest, and Octapharma.Common variable immunodeficiencies (CVID) are a heterogeneous group of disorders characterized by a failure to make antibodies. CVID is by far the most frequent diagnosis within the category of primary antibody deficiencies and accounts for the majority (57%) of symptomatic primary immunodeficiency on the European Society for Immunodeficiencies registry (www.esid.org). CVID is an important diagnosis not only because of its prevalence (1 in 25,000-50,000) but also because of the frequent requirement for medical attention and intervention. The morbidity and the need for health resources is exacerbated by a diagnostic delay of, on average, between 6 and 7 years before appropriate treatment is started.1Cunningham-Rundles C. How I treat common variable immune deficiency.Blood. 2010; 116: 7-15Crossref PubMed Scopus (59) Google Scholar In contrast to many other primary immunodeficiency diseases, patients with CVID may be diagnosed at almost any age, with the majority being recognized between 20 and 40 years of age.1Cunningham-Rundles C. How I treat common variable immune deficiency.Blood. 2010; 116: 7-15Crossref PubMed Scopus (59) Google Scholar This has implications for the methodology and timing of screening approaches aimed at reducing diagnostic delay.The protean manifestations of CVID are reflected in the number of specialties to which these patients may present, and this alongside the wide variation of the noninfectious complications may result in a delay in recognition of the underlying diagnosis. The diagnosis of CVID in the very young is more problematic because it must be differentiated from transient hypogammaglobulinemia of infancy, and this is only possible with the passage of time and in practice when children are older than 4 years of age.2Moschese V. Graziani S. Avanzini M.A. Carsetti R. Marconi M. La Rocca M. et al.A prospective study on children with initial diagnosis of transient hypogammaglobulinemia of infancy: results from the Italian Primary Immunodeficiency Network.Int J Immunopathol Pharmacol. 2008; 21: 343-352Crossref PubMed Google Scholar Advances in genetic tools have allowed the identification of the individual genes for the majority of the well-defined immunodeficiencies over the past 2 decades. There have been remarkable advances in our understanding of the molecular basis of severe combined immunodeficiencies3van der Burg M. Gennery A.R. Educational paper. The expanding clinical and immunological spectrum of severe combined immunodeficiency.Eur J Pediatr. 2011; 170: 561-571Crossref PubMed Scopus (25) Google Scholar and mendelian susceptibility to mycobacterial disease.4Al-Muhsen S. Casanova J.L. The genetic heterogeneity of mendelian susceptibility to mycobacterial diseases.J Allergy Clin Immunol. 2008; 122 (quiz 52-3): 1043-1051Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar In antibody deficiency, mutations in genes that comprise 90% of early B-cell defects have been identified, and, similarly, in the hyper-IgM syndromes, known genes now account for approximately 70% to 80% of patients.Following on from the discovery of the association of particular MHC haplotypes with CVID in the 1990s,5Volanakis J.E. Zhu Z.B. Schaffer F.M. Macon K.J. Palermos J. Barger B.O. et al.Major histocompatibility complex class III genes and susceptibility to immunoglobulin A deficiency and common variable immunodeficiency.J Clin Invest. 1992; 89: 1914-1922Crossref PubMed Google Scholar progress has been painfully slow; however, there now is a small list of monogenic disorders with a CVID-like phenotype, which include ICOS (inducible costimulator),6Grimbacher B. Hutloff A. Schlesier M. Glocker E. Warnatz K. Drager R. et al.Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency.Nat Immunol. 2003; 4: 261-268Crossref PubMed Scopus (375) Google Scholar CD19,7van Zelm M.C. Reisli I. van der Burg M. Castano D. van Noesel C.J. van Tol M.J. et al.An antibody-deficiency syndrome due to mutations in the CD19 gene.N Engl J Med. 2006; 354: 1901-1912Crossref PubMed Scopus (204) Google Scholar BAFFR (B-cell activating factor receptor),8Warnatz K. Salzer U. Rizzi M. Fischer B. Gutenberger S. Bohm J. et al.B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans.Proc Natl Acad Sci U S A. 2009; 106: 13945-13950Crossref PubMed Scopus (104) Google Scholar CD20,9Kuijpers T.W. Bende R.J. Baars P.A. Grummels A. Derks I.A. Dolman K.M. et al.CD20 deficiency in humans results in impaired T cell-independent antibody responses.J Clin Invest. 2010; 120: 214-222Crossref PubMed Scopus (90) Google Scholar CD21,10Thiel J. Kimmig L. Salzer U. Grudzien M. Lebrecht D. Hagena T. et al.Genetic CD21 deficiency is associated with hypogammaglobulinemia.J Allergy Clin Immunol. 2012; 129: 801-810.e6Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar CD81,11van Zelm M.C. Smet J. Adams B. Mascart F. Schandene L. Janssen F. et al.CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency.J Clin Invest. 2010; 120: 1265-1274Crossref PubMed Scopus (92) Google Scholar and LRBA (lipopolysaccharide responsive beige-like anchor protein).12Lopez-Herrera G. Tampella G. Pan-Hammarstrom Q. Herholz P. Trujillo-Vargas C.M. Phadwal K. et al.Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity.Am J Hum Genet. 2012; 90: 986-1001Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar In addition, TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor),13Castigli E. Wilson S.A. Garibyan L. Rachid R. Bonilla F. Schneider L. et al.TACI is mutant in common variable immunodeficiency and IgA deficiency.Nat Genet. 2005; 37: 829-834Crossref PubMed Scopus (338) Google Scholar, 14Salzer U. Chapel H.M. Webster A.D. Pan-Hammarstrom Q. Schmitt-Graeff A. Schlesier M. et al.Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.Nat Genet. 2005; 37: 820-828Crossref PubMed Scopus (321) Google Scholar is believed to be a disease-associated rather than disease-causing gene. Up to now, unravelling the bulk of the molecular causes of CVID has remained elusive, with the exception of TACI (which is found in 8%-10% of patients with CVID and 1% or more of healthy controls), the remaining genes account for fewer than 3% of patients with CVID.15Salzer U. Warnatz K. Peter H.H. Common variable immunodeficiency: an update.Arthritis Res Ther. 2012; 14: 223Crossref PubMed Scopus (12) Google Scholar It is well recognized that, in primary immunodeficiency, there may be considerable clinical heterogeneity even in patients with the same defined mutation. But CVID is yet more complex because not only are the mutations not known, neither are the number of distinct disorders or the key environmental modifiers for this mixed group of single gene and polygenic disorders.The Diagnosis of CVIDClinically, the majority of patients with CVID present with recurrent sinopulmonary bacterial infections16Cunningham-Rundles C. Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients.Clin Immunol. 1999; 92: 34-48Crossref PubMed Scopus (779) Google Scholar and reduced serum levels of IgG, IgA, and/or IgM, with reduced or absent specific-antibody production after test vaccination.17Chapel H. Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions.Br J Haematol. 2009; 145: 709-727Crossref PubMed Scopus (89) Google Scholar The diagnostic criteria for CVID illustrate some of the difficulties faced when there is considerable heterogeneity within a diagnostic category. The criteria18Conley M.E. Notarangelo L.D. Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies).Clin Immunol. 1999; 93: 190-197Crossref PubMed Scopus (450) Google Scholar are: a male or female patient with a marked decrease in IgG (at least 2 SDs below the mean for age) and at least one of the IgA or IgM isotypes; onset of immunodeficiency at more than 2 years of age; the absence of isohemagglutinins and/or poor responses to vaccines; and that other defined causes of hypogammaglobulinemia have been excluded.The diagnosis, therefore, is one of exclusion, there is no clear cutoff for immunoglobulin levels, and “poor” responses to vaccines do not specify what constitutes an adequate response, nor do the diagnostic criteria differentiate between responses to conjugated, T-dependent vaccines, such as those for tetanus, hemophilus, and pneumococcus (Mentorix [GlaxoSmithKline, Uxbridge, UK], Prevenar 13 [Pfizer, Sandwich, UK]), and unconjugated polysaccharide T-independent vaccines (Pneumovax II [Sanofi Pasteur MSD Limited, Maidenhead, UK]) or their durability.The condicio sine qua non to make the diagnosis is a low IgG, and although levels at approximately 4 SDs below the mean at less than 4 g/L in adults are more convincing than levels just below the lower limit of normal of 6 g/L, it remains important to assess responses to vaccination before commencing immunoglobulin replacement therapy. This introduces a delay of 3-4 weeks to await the postvaccination responses, but patients may be treated with prophylactic antibiotics during this period both to offer some protection but also to reduce any chronic lung or sinus infection ahead of immunoglobulin if it is initiated.Diagnostic delayEarly diagnosis and optimal management are likely to result in improved clinical and quality-of-life outcomes for patients with CVID. Reducing diagnostic delay, therefore, is crucial, and approaches include improved education and awareness, particularly regarding the adult onset and variable noninfectious presentations, of clinicians in both primary and secondary care. Unfortunately, the very successful newborn screening for severe combined immunodeficiency that looks for TREC (T-cell receptor excision circles) in DNA extracted from Guthrie spots,19Verbsky J.W. Baker M.W. Grossman W.J. Hintermeyer M. Dasu T. Bonacci B. et al.Newborn screening for severe combined immunodeficiency; the Wisconsin experience (2008-2011).J Clin Immunol. 2012; 32: 82-88Crossref PubMed Scopus (14) Google Scholar when extended to B-cell KREC (κ-deleting recombination excision circles)20Borte S. von Dobeln U. Fasth A. Wang N. Janzi M. Winiarski J. et al.Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR.Blood. 2012; 119: 2552-2555Crossref PubMed Scopus (17) Google Scholar will not detect CVID due to the adult onset and presence of B cells in the majority of patients. Guthrie spots are also unsuitable for the detection of IgA deficiency as a marker in neonates because the IgA is of both fetal and maternal origin.21Borte S. Janzi M. Pan-Hammarstrom Q. von Dobeln U. Nordvall L. Winiarski J. et al.Placental transfer of maternally-derived IgA precludes the use of guthrie card eluates as a screening tool for primary immunodeficiency diseases.PLoS One. 2012; 7: e43419Crossref PubMed Scopus (4) Google Scholar A number of UK centers have started to use calculated globulin (total protein – albumin), which is a component of liver function testing (LFT) as a screen for antibody deficiency. LFTs are performed in very high numbers (just under 2 million/yr for a population of 3.6 million in Wales) and are inexpensive because the inclusion of total protein (if not already included) within the LFT test set costs 7 pence or 11 US cents. By using appropriately established method-dependent cutoff values, it has been possible to detect antibody deficiencies, and patients with CVID found by using this approach have commenced immunoglobulin replacement. By using the bromocresol green methodology for the measurement of albumin,22Corcoran R.M. Durnan S.M. Albumin determination by a modified bromcresol green method.Clin Chem. 1977; 23: 765-766PubMed Google Scholar we found a cutoff value of <18 g/L for calculated globulin defines a population in which 89% have an IgG level of <6 g/L (unpublished data, 2013). Immunology laboratories also have opportunistically detected cases of antibody deficiency by cascade testing for immunoglobulins when there is a very low background in ELISAs used for IgA-based celiac disease testing, such as the tissue transglutaminase assay23Bright P. Lock R.J. Unsworth D.J. Immunoglobulin A deficiency on serological coeliac screening: an opportunity for early diagnosis of hypogammaglobulinaemia.Ann Clin Biochem. 2012; 49: 503-504Crossref PubMed Scopus (2) Google Scholar and also when there is a very low IgE <2 IU/mL.24Unsworth D.J. Virgo P.F. Lock R.J. Immunoglobulin E deficiency: a forgotten clue pointing to possible immunodeficiency?.Ann Clin Biochem. 2011; 48: 459-461Crossref PubMed Scopus (3) Google Scholar Clinical approaches to screening also have involved the use of the “10 warning signs” of primary immunodeficiency and the use of computer sorting of diagnostic codes.25Cunningham-Rundles C. Sidi P. Estrella L. Doucette J. Identifying undiagnosed primary immunodeficiency diseases in minority subjects by using computer sorting of diagnosis codes.J Allergy Clin Immunol. 2004; 113: 747-755Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar A study into the clinical features that identify children with immunodeficiency found that, of the 10 warning signs, the strongest predictors were family history, intravenous antibiotics for sepsis (neutrophil defects), and failure to thrive (T-cell defects), whereas, for B-cell defects, the only predictor was family history of immune deficiency.26Subbarayan A. Colarusso G. Hughes S.M. Gennery A.R. Slatter M. Cant A.J. et al.Clinical features that identify children with primary immunodeficiency diseases.Pediatrics. 2011; 127: 810-816Crossref PubMed Scopus (25) Google ScholarBaseline investigations and monitoringThe varied presentations of CVID are reflected in the diverse routes of referral to immunology from clinicians in respiratory medicine, gastroenterology, hematology, Ear Nose and Throat (ENT), medicine, general practice, rheumatology, and others. Diagnostic testing may have already have taken place, but it is important that, once the patient is referred, initial blood tests are performed centrally in an accredited laboratory, because ongoing monitoring will be referenced to this baseline. Once the diagnosis of CVID is made, there are a number of tests important for the initial workup before commencing immunoglobulin replacement therapy. Baseline testing includes a complete blood cell count; hematinics; a peripheral lymphoma panel; biochemistry renal; LFTs; bone profile; C-reactive protein; immunoglobulins; serum and urine electrophoresis; specific antibodies to tetanus, hemophilus, and pneumococcus; lymphocyte phenotypes with EUROClass B-cell panel and naive T cells; and MBL (mannan binding lectin) (this is not intended to be an exhaustive list of tests and reflects the author's practice). Lung function measurement is performed by using spirometry every 6 months, and extended testing, including gas exchange annually, with chest high-resolution computed topography (HRCT) at entry into the cohort and thereafter as clinically indicated. In stable patients, repeated HRCT is not routine at intervals of less than 5 years. Patients are reviewed on a 6-monthly basis in the clinic if well, by both the immunology specialist nurses and the medical team, and monitoring takes place both at these appointments as well as through send-in monitoring for trough IgG levels, LFTs, and C reactive protein (CRP) every 3 to 4 months. The immunology specialist nurses initially perform annual home visits for those patients infusing immunoglobulin at home followed by two yearly visits if stable, and emergency appointment slots are available if needed. Further investigations of the lungs, gut, autoimmunity, lymphoproliferation, or other systems are driven by the presentation, existing disease, and ongoing evaluation. It is expected that details of practice will vary among centers and countries.Clinical Phenotypes and BiomarkersMortality in CVID was reported in the 1990s at 23% (56/248) during a follow-up of 1-20 years (mean, 7.5 years),27Healy M.J. Hypogammaglobulinaemia in the United Kingdom. XII. Statistical analyses: prevalence, mortality and effects of treatment.Spec Rep Ser Med Res Counc (G B). 1971; 310: 115-123PubMed Google Scholar alongside reduced survival versus with age-matched controls for the same period, of 64% versus 92% for male patients and 67% versus 94% for female patients. About the same time, figures from the United Kingdom were similar with a 30% mortality in a cohort of 240 patients followed up for 25 years.28Hermaszewski R.A. Webster A.D. Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications.Q J Med. 1993; 86: 31-42PubMed Google Scholar Over time, there has been a clear improvement in survival of patients with CVID shown in European figures from the European Society for Immunodeficiencies registry, in which 15% of patients (51/334) died over a longer mean follow-up period of 22.5 years.1Cunningham-Rundles C. How I treat common variable immune deficiency.Blood. 2010; 116: 7-15Crossref PubMed Scopus (59) Google Scholar That having been said, the overall survival of both male and female patients with CVID remains considerably lower than that of age-matched controls.29Resnick E.S. Moshier E.L. Godbold J.H. Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades.Blood. 2012; 119: 1650-1657Crossref PubMed Scopus (43) Google ScholarThe major reason to subdivide CVID into clinical phenotypes is to better predict disease course and complications, thus improving management in the absence of defined genetic diagnoses for this group of disorders. In addition clear and stable clinical phenotypes allow comparison of more homogenous groups of patients within studies. Clinical phenotypes have been described after analysis of large CVID cohorts30Chapel H. Lucas M. Lee M. Bjorkander J. Webster D. Grimbacher B. et al.Common variable immunodeficiency disorders: division into distinct clinical phenotypes.Blood. 2008; 112: 277-286Crossref PubMed Scopus (178) Google Scholar and further refined into 4 phenotypes31Chapel H. Lucas M. Patel S. Lee M. Cunningham-Rundles C. Resnick E. et al.Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts.J Allergy Clin Immunol. 2012; 130 (1197–8.e9)PubMed Google Scholar: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 enteropathyIt is clear that the phenotypes define significant differences in biology as the presence of one or more noninfectious complications is associated with an almost 11-fold increase in mortality during follow-up.29Resnick E.S. Moshier E.L. Godbold J.H. Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades.Blood. 2012; 119: 1650-1657Crossref PubMed Scopus (43) Google Scholar, 30Chapel H. Lucas M. Lee M. Bjorkander J. Webster D. Grimbacher B. et al.Common variable immunodeficiency disorders: division into distinct clinical phenotypes.Blood. 2008; 112: 277-286Crossref PubMed Scopus (178) Google Scholar Patients with no other disease-related complications had a long-term survival of 95% versus 42% in those with noninfectious complications.29Resnick E.S. Moshier E.L. Godbold J.H. Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades.Blood. 2012; 119: 1650-1657Crossref PubMed Scopus (43) Google Scholar The phenotypes appeared distinct in patients from 2 European and 1 American cohort, with 89% to 94% fitting into a single phenotype.31Chapel H. Lucas M. Patel S. Lee M. Cunningham-Rundles C. Resnick E. et al.Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts.J Allergy Clin Immunol. 2012; 130 (1197–8.e9)PubMed Google Scholar The proportions of the phenotypes (Figure 1) and the effects on survival were most marked for enteropathy, followed by lymphoproliferation and cytopenias.31Chapel H. Lucas M. Patel S. Lee M. Cunningham-Rundles C. Resnick E. et al.Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts.J Allergy Clin Immunol. 2012; 130 (1197–8.e9)PubMed Google Scholar An analysis of geographically distinct cohorts shows wide variation with, for example, Swedish patients having much lower prevalence of lymphoproliferative complications, 12%, than those in the Czech Republic, at 54%.30Chapel H. Lucas M. Lee M. Bjorkander J. Webster D. Grimbacher B. et al.Common variable immunodeficiency disorders: division into distinct clinical phenotypes.Blood. 2008; 112: 277-286Crossref PubMed Scopus (178) Google Scholar These differences are likely to reflect the effects of distinct genetic backgrounds on the expression of the phenotypes, although differences in the care of these different groups, for example, intensity of prophylactic antibiotic use, must also be considered.When autoimmune manifestations were separated into cytopenias and organ-specific autoimmunity, it was found that only cytopenias were associated with reduced survival,31Chapel H. Lucas M. Patel S. Lee M. Cunningham-Rundles C. Resnick E. et al.Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts.J Allergy Clin Immunol. 2012; 130 (1197–8.e9)PubMed Google Scholar and, in another large study, no decrease in survival was noted with autoimmunity.29Resnick E.S. Moshier E.L. Godbold J.H. Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades.Blood. 2012; 119: 1650-1657Crossref PubMed Scopus (43) Google Scholar The lymphoproliferative expansion of cells into the tissues manifests as noncaseating granulomas in 8% to 22% of patients, predominantly in the lungs, lymph nodes, liver, and spleen but also in other sites, including the brain.29Resnick E.S. Moshier E.L. Godbold J.H. Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades.Blood. 2012; 119: 1650-1657Crossref PubMed Scopus (43) Google Scholar, 32Ardeniz O. Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency.Clin Immunol. 2009; 133: 198-207Crossref PubMed Scopus (45) Google Scholar The finding of granulomas often predates the diagnosis of CVID and may then be mistakenly diagnosed as sarcoidosis.33Arnold D.F. Wiggins J. Cunningham-Rundles C. Misbah S.A. Chapel H.M. Granulomatous disease: distinguishing primary antibody disease from sarcoidosis.Clin Immunol. 2008; 128: 18-22Crossref PubMed Scopus (20) Google Scholar Splenomegaly can be massive in CVID, sometimes necessitating splenectomy for cytopenias or pain, and a recent retrospective study of 45 cases of splenectomy in CVID offers reassurance that this was an effective treatment in 75% of patients and did not result in increased mortality.34Wong G.K. Goldacker S. Winterhalter C. Grimbacher B. Chapel H. Lucas M. et al.Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients.Clin Exp Immunol. 2013; 172: 63-72Crossref PubMed Scopus (4) Google Scholar It is likely that rituximab therapy for cytopenias may reduce the need for splenectomy. Therapy of the lymphoproliferative and inflammatory complications, particularly as they affect the lungs, gut, and liver, is a challenging balancing act because immunosuppressive treatments are needed to minimize inflammatory damage in the setting of immunodeficiency. It also should be noted that lymphoproliferation, at least in part, can be a response to infection and that optimization of therapy with pulmonary hygiene, prophylactic antibiotics, early and quick attention to common infection, and appropriate adjustment of immunoglobulin replacement may be of some benefit.Laboratory testing such as the EUROClass B-cell flow cytometric classification system35Wehr C. Kivioja T. Schmitt C. Ferry B. Witte T. Eren E. et al.The EUROclass trial: defining subgroups in common variable immunodeficiency.Blood. 2008; 111: 77-85Crossref PubMed Scopus (200) Google Scholar has developed the key" @default.
• W2024897191 created "2016-06-24" @default.
• W2024897191 creator A5005453736 @default.
• W2024897191 date "2013-11-01" @default.
• W2024897191 modified "2023-09-27" @default.
• W2024897191 title "The Variable in Common Variable Immunodeficiency: A Disease of Complex Phenotypes" @default.
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