Graphical AbstractĪ pathophysiologic hallmark and likely a key mechanism of immune suppression in sepsis is a profound apoptosis-induced depletion of lymphocytes. Because of equivalent positive laboratory and clinical responses, more favorable pharmacokinetics, and better patient tolerability, intramuscular administration of CYT107 is preferable. However, compared to intramuscular CYT107 administration, it was associated with transient respiratory distress without long-term sequelae. Intravenous CYT107 reversed sepsis-induced lymphopenia. No cytokine storm and no formation of antibodies to CYT107 were observed. However, intravenous CYT107 produced an approximately 100-fold increase in CYT107 blood concentration compared with intramuscular CYT107. This increase was similar to that seen with intramuscular administration of CYT107, was maintained throughout follow-up, reversed severe lymphopenia and was associated with increase in organ support free days (OSFD). Intravenous administration of CYT107 resulted in a two–threefold increase in absolute lymphocyte counts (including in both CD4 + and CD8 + T cells (all p < 0.05)) compared to placebo. The study was halted early because three of fifteen patients receiving intravenous CYT107 developed fever and respiratory distress approximately 5–8 h after drug administration. Twenty-one patients were enrolled (fifteen CYT107 group, six placebo group) at eight French and two US sites. This prospective, double-blinded, placebo-controlled trial was designed to enroll 40 sepsis patients, randomized 3:1 to CYT107 (10 µg/kg) or placebo, for up to 90 days. Thepresent study evaluated intravenous administration of CYT107. A previous phase II study showed that CYT107, a glycosylated recombinant human IL-7, administered intramuscularly reversed sepsis-induced lymphopenia and improved lymphocyte function. Interleukin-7 (IL-7) is essential for lymphocyte proliferation and survival. Profound lymphopenia is an independent predictor of adverse clinical outcomes in sepsis.
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