Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency, marked by hypogammaglobulinemia, poor antibody responses, and increased infection susceptibility. The COVID-19 pandemic provided a unique opportunity to study the effects of prolonged viral infections on the immune responses of CVID patients. Here we use single-cell RNA-seq and spectral flow cytometry of peripheral blood samples before, during, and after SARS-CoV-2 infection showing that COVID-19 CVID patients display a persistent type I interferon signature at convalescence across immune compartments. Alterations in adaptive immunity include sustained activation of naïve B cells, increased CD21low B cells, impaired Th1 polarization, CD4+ T central memory exhaustion, and increased CD8+ T cell cytotoxicity. NK cell differentiation is defective, although cytotoxicity remains intact. Monocytes show persistent activation of inflammasome-related genes. These findings suggest the involvement of intact humoral immunity in regulating these processes and might indicate the need for early intervention to manage viral infections in CVID patients. Common variable immunodeficiency (CVID) is a prevalent primary immunodeficiency characterized by hypogammaglobulinemia, poor antibody responses, and enhanced susceptibility to infection. Here the authors examine CVID patients infected by SARS-CoV-2 and describe broad immune dysregulation, sustained type I IFN responses, altered B/T cell signaling, impaired NK cell differentiation, and persistent inflammasome activation.

COVID-19 progression and convalescence in common variable immunodeficiency patients show dysregulated adaptive immune responses and persistent type I interferon and inflammasome activation