All Patients With Common Variable Immunodeficiency Disorders (CVID) Should Be Routinely Offered Diagnostic Genetic Testing.

Abstract

Common Variable Immunodeficiency Disorders (CVID) are a rare group of primary immunodeficiency disorders (PIDs) where late onset antibody failure leads to immune system failure (1). Onset of symptoms can occur from early childhood to the eighth decade or later (2). Current estimates suggest a prevalence between 1: 25 000 to 1: 100 000 in Caucasians (3, 4). For reasons that are unclear, CVID appears to be less frequent in Asian and African populations, although there may be ascertainment bias. The majority of patients with CVID present with recurrent and severe infections. Untreated, patients are predisposed to chronic suppuration of the respiratory tract, often resulting in chronic sinus disease and bronchiectasis. Approximately 25% of CVID patients suffer autoimmune or inflammatory sequelae, consequent to immune dysregulation (5). There is also an increased risk of malignancy (6). There is no single clinical feature or laboratory test, which is pathognomonic for CVID. The identification of CVID therefore relies on diagnostic criteria. There are currently three new sets of diagnostic criteria for CVID (7–9). The Ameratunga et al. (7) criteria require symptomatic primary hypogammaglobulinemia with relevant laboratory tests to establish the diagnosis. The threshold for IgG was set at 5 g/l for adults. The revised European Society for immunodeficiencies (8) are similar to the Ameratunga et al. criteria. The most recent International Consensus Document (9) CVID criteria claim to be able to make a definite diagnosis on the basis of a single abnormal vaccine challenge result in a patient with primary hypogammaglobulinemia (9). The latter two criteria have set the threshold for IgG at 2 sd below the mean. Although immunoglobulin levels do not follow a Gaussian distribution (10), this is generally accepted as an IgG below 7 g/l. These criteria also exclude late onset combined immunodeficiency (LOCID) from the diagnosis. The immunoglobulin levels are also required to be repeated in these latter criteria. There is ongoing debate about the utility these diagnostic criteria, the variability of IgG levels over time, the unreliability of vaccine challenge responses and flow cytometry in the diagnosis of CVID. As discussed below, this variability in protein-based assays is a strong argument for genetic testing of all patients with a CVID phenotype.