Severe Lymphopenia Is Associated with Elevated Plasma Interleukin-15 Levels and Increased Mortality During Severe Sepsis

Abstract

Sepsis-related mortality has been found increased in RAG-1 knockout mice. However, in patients admitted to medical intensive care units, it is unknown whether severe lymphocyte depletion at admission is associated with increased interleukin (IL)-7 and IL-15 levels in circulation, and increased mortality. We prospectively enrolled 92 patients who were admitted to medical intensive care units for severe sepsis or septic shock. At admission, 24 patients (26.1%) had severe lymphopenia, defined as lymphocyte counts of less than 0.5 × 10(3)/μL. Severe lymphopenia was associated with significantly higher plasma levels of tumor necrosis factor α, IL-6, IL-8, and IL-10 and was also independently associated with 28-day mortality (adjusted hazard ratio, 3.532; 95% confidence interval, 1.482-8.416; P = 0.004). The levels of plasma IL-15, but not IL-7, were increased modestly in patients with severe lymphopenia compared with those without (median, 12.2 vs. 6.4 pg/mL; P = 0.005). The elevated plasma IL-15 levels were contrarily associated with significantly decreased B-cell lymphoma 2 mRNA expression in peripheral blood mononuclear cells. In conclusion, severe lymphopenia was associated with increased mortality in patients with severe sepsis. We found that patients with sepsis with severe lymphopenia had down-regulated B-cell lymphoma 2 mRNA expression in peripheral blood mononuclear cells, despite increased plasma IL-15 concentrations. Whether IL-7 and IL-15 are insufficient in patients with severe lymphopenia during severe sepsis warrants further investigations.

Chronic Critical Illness from Sepsis Is Associated with an Enhanced TCR Response

“…Given that sepsis is generally accompanied by acute lymphopenia (17,52,53), these findings suggested that sepsis survivors replenish the hole created in their T cell compartment. Several studies reported an association between T cell numbers and prognosis of sepsis patients beyond the acute disease phase (17,54,55), leading to the proposal that persistent lymphopenia could serve as a biomarker for late mortality in sepsis (17,55). In principle, the absence of lymphopenia in the present patient cohort is in agreement with that notion, given that all 12 patients were alive at the 28-d follow-up upon discharge from the postacute care hospital (Table II).…”

“…Another factor that is likely to persistently affect the adaptive immune system of the sepsis patient is the contraction of the T cell clonal repertoire as a consequence of early apoptotic T cell loss. As argued previously (17,22,55), the irreversible loss of T cell clones during early sepsis causes a contraction of the T cell repertoire that can compromise the ability of the host to react to ensuing infections. According to that scenario, "prosurvival" cytokines, such as IL-7 or IL-15, which prevent early T cell apoptosis and show high efficacy in rodent models of sepsis (13,56,73), are promising therapeutics that are already being tested in the clinic.…”

Dying to protect: cell death and the control of T‐cell homeostasis

“…In sepsis, IL-15 blocked the apoptosis of CD8 + T cells and increased the abundance of Bcl-2 while decreasing Bim and Puma (343). However, patients with sepsis with severe lymphopenia had downregulated Bcl-2 mRNA expression in peripheral blood mononuclear cells, despite increased plasma IL-15 concentrations (344). Thus, further studies are needed to understand the potential role of IL-15 in sepsis.…”

Sepsis‐induced immune alterations monitoring by flow cytometry as a promising tool for individualized therapy

“…Every lymphocyte subpopulation was affected (except regulatory T cells, see below). Most importantly, the extent of this lymphopenia has been shown to correlate with the development of HAI and/or death at 28 days . Importantly, this lymphopenia may last for several weeks after the onset of sepsis and this lack of recovery was associated with delayed infectious complications .…”