Immunologic biomarkers of noninfectious complications and overall survival in common variable immunodeficiency

Background: Common variable immunodeficiency (CVID) includes a heterogeneous group of disorders of predominantly antibody deficiencies featuring infectious and noninfectious complications that might lead to severe organ damage and shortened survival. Appropriate clinical management of CVID has been hampered by the lack of robust biomarkers to predict the development of clinical complications and patient outcome. Objective: We investigated the association of individual serologic, cellular, and molecular biomarkers with disease behavior and outcome in CVID. Methods: A multicenter cohort of 209 CVID patients was studied using age-matched reference values from 334 healthy donors to better define TCD4+-naive cell defects (late-onset combined immunodeficiency LOCID) and classify CVID-associated B-cell/plasma cell (PC) and natural killer (NK) cell defects. Results: Globally, susceptibility to respiratory infections was strongly associated with low serum immunoglobulin (sIg), particularly sIgA, whereas noninfectious complications and disease severity mostly depended on TCD4+-naive cell, NK cell, and B-cell/PC defects. LOCID was independently associated with splenomegaly, lymphadenopathy, interstitial lung disease, cytopenia, and lymphoma. Milder B-cell/PC defects (MBC+/PC+/Ab−) protected from noninfectious complications, whereas a marked defect of classical CD27+ memory B cells (27MBC−) (with decreased NK cell and sIgM) was associated with enteropathy and (with LOCID and sIgA) liver disease. Together, lower sIgG, LOCID, and particularly 27MBC−, were strongly associated with shorter survival and early death in CVID. Conversely, CVID-associated pathogenic/risk alleles did not emerge as independent factors associated with disease behavior and outcome. Conclusion: Our results provide a new set of biomarkers closely associated with infectious and noninfectious complications of CVID, which together predict survival and might contribute to guide patient monitoring and clinical management.