The variable in common variable immunodeficiency: a disease of complex phenotypes.

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.