Review and Feature Article
International Consensus Document (ICON): Common Variable Immunodeficiency Disorders

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Definition

The term “common variable immunodeficiency” (CVID) was coined in 1971 by a World Health Organization committee to separate less well-defined antibody deficiency syndromes from others with a more coherent clinical description and Mendelian inheritance.1, 2 Therefore, the hypogammaglobulinemic syndrome of CVID became a diagnosis of exclusion. Since then, the International Union of Immunological Societies Expert Primary Immunodeficiency Committee redefined the conditions in 2009 as “common

Epidemiology

Primary immunodeficiency disorders are usually considered to be “rare diseases.” However, as a whole, this group of diseases may not be as rare as once thought. Neither the true incidence nor the true prevalence of primary immunodeficiency is known. Most studies are geographically limited and based on survey data or record review of diagnosed and/or registered cases.17, 18, 19, 20, 21 The number of undiagnosed cases is unknown because a comprehensive population-based screening process for

Pathogenesis

With the exception of some known monogenic forms of CVID (discussed below), no cause for the immune defect has been found in 98% of the patients with CVID. With the hallmark of hypogammaglobulinemia, the immune defect common to all patients with CVID is loss of B-cell function. This is either intrinsic to B cells, or a result of insufficient help from other cells for antibody production. In particular, there is a reduction in the number and percentage of isotype-switched B cells in a majority

Genetics

CVID is a complex, multifocal disease, the genetic origins of which are beginning to be at least partially understood. Most cases of CVID are sporadic. Approximately 5% to 25% are familial, with an autosomal-dominant pattern of inheritance being more frequently observed.51, 126 Rarely, families exhibiting autosomal-recessive inheritance have been reported.

A number of studies concentrated on CVID/IgAD families revealed several putative susceptibility loci identified within the HLA region on

Diagnosis

Clinicians must maintain an index of suspicion for antibody deficiency in patients of all ages. Conditions associated with acquired hypogammaglobulinemia should always be considered during the evaluation of a patient with a suspected antibody deficiency. These include drugs (chronic glucocorticosteroid use, antiepileptic drugs, rituximab therapy), malignancies (chronic lymphocytic leukemia, lymphomas), nephrotic syndrome, protein-losing enteropathy, and congenital lymphangiectasias. See Table I

Immunoglobulin replacement therapy

IgG can be given by intravenous or subcutaneous route and at varying intervals to suit the patient's specific needs.184 Both types of preparations are efficacious, safe for infusion at home, and widely available, being on the World Health Organization Essential Medicines Lists for adults and children. Patients require monitoring of breakthrough bacterial infections and serum trough or steady-state IgG levels because each individual has a unique threshold level of IgG to prevent breakthrough

Prognosis

In the first UK Medical Research Council Report in 1979, survival of patients with CVID 12 years after diagnosis was only 30%.251 By the end of the 1990s, with the advent of high-dose IVIG therapy, survival 20 years after diagnosis was 64% for males and 67% for females, as compared with the expected 92% and 94% population survival, respectively.52 Since the year 2000, as the standard replacement dose of IgG has steadily increased, more and more patients have had more normal IgG levels for the

Definition

It is evident from this work and other publications16 that full consensus regarding the definition of CVID does not yet exist. Some groups include clinical criteria in the definition, however, as for other primary immune defects, and considering the diverse manifestations of this disease, we conclude that the diagnosis of CVID should be primarily based on laboratory criteria. It is possible that advances in the areas of biomarkers and genetics (see below) will provide new material for or a new

Acknowledgment

We respectfully and fondly dedicate this work to the memory of our colleague, coauthor, and friend Dr Isil Barlan.

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    This article is a product of an international coalition between the American Academy of Allergy, Asthma & Immunology; the European Academy of Allergy and Clinical Immunology; the World Allergy Organization; and the American College of Allergy, Asthma & Immunology on common variable immunodeficiency.

    Conflicts of interest: F. A. Bonilla is on the Immune Deficiency Foundation Board; has received consultancy fees from Baxter, The Cowan Group Inc, CSL Behring, Gerson-Lehrman Group Inc, Grand Rounds Health Inc, and the Immune Deficiency Foundation; has received research support from CSL Behring; has received lecture fees from Albany Medical College, Finger Lakes Allergy Society, and Eastern Allergy Conference; received royalties from UpToDate; has received travel support from American Public Health Laboratories; and has received other funds from Octapharma Inc. H. Chapel is on the Baxter board and has received consultancy fees from Biotest and LFB. M. T. de la Morena has received consultancy fees from the Atlantic Research Group. F. J. Espinosa-Rosalesis on the Baxter board; has received lecture fees from Grifols and CSL Behring; and has received travel support from Grifols, CSL Behring, and Octapharma. I. Quinti is on the Baxter board; has received consultancy fees from FKB; has received research support from the Plasma Protein Therapeutics Association; has received lecture fees from Baxter and Kedrion; and has received travel support from Baxter. J. M. Routes has received research support from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (granulomatous lymphocytic interstitial lung disease in common variable immunodeficiency grant—R34 planning grant). M. L. K. Tang is on the Nestle Nutrition Institute Medical Advisory Board Oceania; is on the Danone Nutritia Medical Advisory Board Australia New Zealand and Global Scientific Advisory Board; has received consultancy fees from GLG Consultants and Deerfield Institute; has received lecture fees from Danone Nutricia and Health Ed; has a patent on a method for inducing tolerance; received royalties from Wiley as a coauthor of Kids Food Allergies for Dummies; and has received payment for developing an educational module for MD Linx. K. Warnatz has received lecture fees from Baxter, GlaxoSmithKline, CSL Behring, Pfizer, the American Academy of Allergy, Asthma & Immunology, Biotest, Novartis, Stallergenes, Roche, Meridian Health Comms, and Octapharma; has received payment for manuscript preparation from UCB Pharma; and has received payment for developing educational presentations from the European Society for Immunodeficiency. The rest of the authors declare that they have no relevant conflicts of interest.

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