Assessing Disease Severity in Common Variable Immunodeficiency Disorders (CVID) and CVID-Like Disorders

Common Variable Immunodeficiency Disorders (CVID) are the most frequent symptomatic primary immune deficiency (PID) in adults. Current estimates suggest a prevalence of ~1:25,000, although a recent study has suggested an even greater frequency than previous estimates (1). The majority of CVID patients suffer recurrent infections because of late onset antibody failure (LOAF) leading to immune system failure (ISF). Current criteria do not allow CVID to be diagnosed before 4 years although some patients have symptoms dating back to infancy. Most patients experience recurrent or severe bacterial infections and less commonly autoimmunity as a result of CVID. Some patients present with a sarcoidosis-like disorder or enteritis (2, 3). A proportion of patients with CVID have a prominent T cell defect leading to severe viral or opportunistic infections. These patients have been deemed to have late onset combined immunodeficiency (LOCID) (4). LOCID is currently separated from CVID although I have argued LOCID should be included as a subset of CVID (5). In spite of major progress in the last decade, the genetic basis of CVID is unknown in most patients. A causative mutation has been identified in up to 30% (6). If a causative defect is identified, these patients are removed from the umbrella diagnosis of CVID and are reclassified as having a CVID-like disorder caused by a specific mutation. To fulfill a diagnosis, all current CVID criteria require exclusion of other immunodeficiencies including NFKB1, NFKB1, CTLA4 etc. It is however likely earlier series of patients with CVID included many with CVID-like disorders, whose mutations were undiscovered. We have recently discovered new genetic defects in two NZ families with CVID-like disorders. In the first family, we have confirmed the existence of quantitative epistasis in humans (7). Epistasis is the non-linear, synergistic interaction of two or more genetic loci either leading to a much more severe disorder or a novel phenotype (8, 9). The existence of epistasis was first predicted by William Bateson in 1909 but has remained highly controversial because of the lack of well characterized examples in humans (10). In this family, the synergistic interaction of TNFRSF13B/TACI and TCF3 mutations resulted in a severe immunodeficiency and systemic lupus erythematosus (SLE) in the proband (Figure ​(Figure1). 1). Other members of the family who have various permutations of the two mutated genes had a milder phenotype, which was reflected in their in vitro B cell differentiation and antibody production studies (7). Open in a separate window Figure 1 Family with a digenic CVID-like disorder caused by epistatic interactions of TNFRSF13B/TACI and TCF3 genes. The proband (arrow) suffers from both a severe immunodeficiency as well as SLE. Other members are as described in our previous publications including a mild symptomatic brother (II.3) with severe hypogammaglobulinemia caused by homozygous C104R mutations of the TNFRSF13B/TACI gene. CDSS, CVID disease severity score; CS, clinical score. The CS was suggested as means of determining eligibility for SCIG/IVIG but we have used it as a surrogate marker of disease severity (5, 7, 11).