The study has been approved by ESID.
Proposed by: Dr. Antonios Gkantaras, Prof. Dr. Markus Seidel
Common Variable Immunodeficiency (CVID) is an “umbrella” diagnosis encompassing a wide spectrum of predominantly antibody deficiencies with marked clinical, immunological and genetic heterogeneity (1). The development of diagnostic criteria has been essential to navigate this heterogeneity, improving diagnostic precision and guiding clinical decision-making (2,3).
Simultaneously, the genetic landscape of CVID is rapidly evolving: although historically fewer than 20% of patients were found to have a defined monogenic cause, with the wide application of next-generation sequencing (NGS) recent studies have demonstrated higher detection rates of monogenic (or oligogenic) defects in CVID, especially in pediatric cohorts (4,5). Adding to the diagnostic complexity, identification of a pathogenic variant associated with an Inborn Error of Immunity (IEI) often leads to reclassification of the patient from CVID to a distinct genetically defined IEI – sometime even in a different IUIS category. This is illustrated in the ESID Registry, where 27% of children and 8% of adults initially diagnosed with CVID were reclassified into over 20 distinct IEI diagnoses, after applying stringent clinical criteria and incorporating genetic testing results (6).
Despite this evolving landscape, major gaps remain—particularly regarding the validity of a CVID diagnosis in pediatric patients. Diagnosis in young children remains contentious, as immune system maturation, transient hypogammaglobulinemia of infancy, and other pediatric-specific immune dynamics raise the question of whether adult-derived CVID criteria are fully applicable (1). While the genetic background of CVID is being better characterized, systematic comparisons of genetic architecture—including frequency of monogenic variants, penetrance, and oligogenic/polygenic contribution—across age strata remain scarce. Moreover, although age-stratified clinical differences have been reported between pediatric-onset and adult-onset CVID (7-9), few large-scale or multicenter studies have systematically examined how genetic status interacts with age at diagnosis (or onset of symptoms) to shape presenting phenotypes.
Taken together, these gaps highlight the need for a retrospective large-cohort analysis, such as that possible with the ESID Registry data, to compare genetic background and clinical manifestations among children and adults with a clinical diagnosis of CVID.
