Common variable immunodeficiency (CVID)

CVID is a heterogeneous antibody-deficiency disorder characterised by recurrent infections and immune dysregulation. Recurrent upper and lower respiratory tract infections are present at diagnosis in 75% of individuals, and severe bacterial infections, including osteomyelitis, meningitis, septicaemia, and mastoiditis, occur in a substantial minority. Bronchiectasis develops in 28% of individuals, while lymphadenopathy (27%), splenomegaly (13%), inflammatory bowel disease (11%), and autoimmune cytopenia (10%) are also commonly reported. A bimodal sex distribution is observed, with male predominance in childhood and female predominance in adulthood. Clinical presentation shows marked inter- and intra-individual variability; 25% of paediatric and 62% of adult individuals develop additional non-infectious manifestations, including granulomatous-lymphocytic interstitial lung disease and inflammatory bowel disease, with immune dysregulation features being more prominent in adults.

Common variable immunodeficiency (CVID) is among the most common primary immunodeficiencies, with an estimated prevalence of approximately 1 in 25,000 to 1 in 50,000 individuals, although prevalence estimates vary between populations and may be influenced by underdiagnosis and diagnostic delay.

CVID is genetically heterogeneous. Germline pathogenic variants in several genes involved in B-cell development, immune regulation, and intracellular signalling have been identified in a subset of individuals with CVID or CVID-like disease. Recurrently implicated genes include TNFRSF13B, TNFRSF13C, NFKB1, NFKB2, CTLA4, LRBA, PIK3CD, PIK3R1, ICOS, CD19, and IKZF1. The underlying molecular mechanisms are diverse and include defects in B-cell maturation, immune homeostasis, and intracellular signalling pathways.

Inheritance in CVID is heterogeneous and depends on the underlying genetic cause. Monogenic forms may follow either autosomal dominant or autosomal recessive inheritance patterns, depending on the gene involved, whereas many cases remain sporadic or lack an identifiable monogenic cause.

The diagnosis of CVID is primarily established according to , which are widely used for clinical diagnosis. Additional diagnostic frameworks include the and the .

• Establishing the diagnosis: Identification of a pathogenic variant may support the clinical diagnosis and help establish an underlying monogenic cause in individuals with a CVID or CVID-like phenotype.
• Clinical management: Knowledge of the underlying genetic cause may inform clinical management and, in selected cases, guide targeted therapeutic approaches and disease surveillance strategies.
• Family member testing: Once a pathogenic variant has been identified in an affected individual, predictive testing of at-risk relatives becomes possible and enables informed genetic counselling.

• Ryan P, Redenbaugh V, McGucken J, Kindle G, Devlin LA, Coulter T, et al. Inborn errors of immunity on the Island of Ireland: a cross-jurisdictional UKPID/ESID Registry Report.  J Clin Immunol. 2022 Aug;42(6):1293-1299. doi: 10.1007/s10875-022-01274-w. Epub 2022 May 23. Erratum in: J Clin Immunol. 2022 Aug;42(6):1300. doi: 10.1007/s10875-022-01306-5. PMID: ; PMCID: PMC9125543.
• Ameratunga R, Longhurst H, Steele R, Woon ST. Comparison of diagnostic criteria for common variable immunodeficiency disorders (CVID) in the New Zealand CVID Cohort Study. Clin Rev Allergy Immunol. 2021;61(2):236-44. doi:10.1007/s12016-021-08860-7. PMID:.
• Janssen LMA, van der Flier M, de Vries E. Lessons learned from the clinical presentation of common variable immunodeficiency disorders: a systematic review and meta-analysis. Front Immunol. 2021;12:620709. doi:10.3389/fimmu.2021.620709. PMID:; PMCID: PMC8021796.
• Vorsteveld EE, Hoischen A, van der Made CI. Next-generation sequencing in the field of primary immunodeficiencies: current yield, challenges, and future perspectives. Clin Rev Allergy Immunol. 2021;61(2):212-25. doi:10.1007/s12016-021-08838-5. PMID:; PMCID: PMC7934351.
• Remiker A, Bolling K, Verbsky J. Common variable immunodeficiency. Med Clin North Am.  2024 Jan;108(1):107-121. doi: 10.1016/j.mcna.2023.06.012. Epub 2023 Jul 21. PMID: .