Human Cytomegalovirus Infection Induces Long-Term Changes in the Cytokine Milieu of Kidney Transplant Recipients

The impact of human cytomegalovirus (HCMV) infection on the mid- and long-term balance between pro-inflammatory and anti-inflammatory cytokines among kidney transplant recipients (KTRs) remains unclear. We measured plasma levels of 12 Th1/Th2-type cytokines (granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin [IL]-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-18 and tumor necrosis factor-α) in a cohort of 290 KTRs at four time points through month 12 after transplantation. Cytokine levels at each point were compared according to the previous documentation of HCMV replication by two approaches: "cumulative exposure" from the time of transplantation and "recent exposure" within the 2-3 months preceding cytokine assessment. Significance levels were Bonferroni-corrected for multiple pairwise comparisons. Plasma levels of IL-6, IL-10, and IL-12p70 at month 1 were significantly increased in KTRs that had experienced HCMV infection during the first 30 days. By month 3, IL-6 and IL-10 remained increased in KTRs with cumulative exposure through day 90. Cumulative exposure to HCMV replication through day 180 was also associated to increased IL-10 levels at month 6. In addition, KTRs with recent HCMV exposure had increased IL-10 levels at months 3 and 6. After multivariable adjustment, cumulative exposure to HCMV infection and/or the area under curve of HCMV DNAemia during the corresponding period were associated to IL-10 levels within the highest quartile at months 1, 3, and 6. Preceding HCMV infection induces sustained changes in the plasma cytokine milieu of KTRs, with elevated IL-6 and IL-10 levels throughout the first 6 months after transplantation.