Persistent lymphopenia after diagnosis of sepsis predicts mortality.

OBJECTIVE: The objective of this study was to determine whether persistent lymphopenia on the fourth day following the diagnosis of sepsis predicts mortality. METHODS: This was a single-center, retrospective cohort study of 335 adult patients with bacteremia and sepsis admitted to a large university-affiliated tertiary care hospital between January 1, 2010, and July 31, 2012. All complete blood cell count profiles during the first 4 days following the diagnosis of sepsis were recorded. The primary outcome was 28-day mortality. Secondary outcomes included development of secondary infections, 1-year mortality, and hospital and intensive care unit lengths of stay. RESULTS: Seventy-six patients (22.7%) died within 28 days. Lymphopenia was present in 28-day survivors (median, 0.7 × 10 cells/µL; interquartile range [IQR], 0.4-1.1 × 10 cells/µL) and nonsurvivors (median, 0.6 × 10 cells/µL; IQR, 0.4-1.1 × 10 cells/µL) at the onset of sepsis and was not significantly different between the groups (P = 0.35). By day 4, the median absolute lymphocyte count was significantly higher in survivors compared with nonsurvivors (1.1 × 10 cells/µL [IQR, 0.7-1.5 × 10 cells/µL] vs. 0.7 × 10 cells/µL [IQR, 0.5-1.0 × 10 cells/µL]; P < 0.0001). Using logistic regression to account for potentially confounding factors (including age, Acute Physiology and Chronic Health Evaluation II score, comorbidities, surgical procedure during the study period, and time until appropriate antibiotic administration), day 4 absolute lymphocyte count was found to be independently associated with 28-day survival (adjusted odds ratio, 0.68 [95% confidence interval, 0.51-0.91]) and 1-year survival (adjusted odds ratio, 0.74 [95% confidence interval, 0.59-0.93]). Severe persistent lymphopenia (defined as an absolute lymphocyte count of 0.6 × 10 cells/µL or less on the fourth day after sepsis diagnosis) was associated with increased development of secondary infections (P = 0.04). CONCLUSIONS: Persistent lymphopenia on the fourth day following the diagnosis of sepsis predicts early and late mortality and may serve as a biomarker for sepsis-induced immunosuppression.

Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis.

INTRODUCTION: Fungal sepsis is an increasingly common problem in intensive care unit patients.Mortality from fungal sepsis remains high despite antimicrobial therapy that is highly active against most fungal pathogens, a finding consistent with defective host immunity that is present in many patients with disseminated fungemia.One recently recognized immunologic defect that occurs in patients with sepsis is T cell "exhaustion" due to increased expression of programmed cell death -1 (PD-1).This study tested the ability of anti-PD-1 and anti-programmed cell death ligand -1 (anti-PD-L1) antagonistic antibodies to improve survival and reverse sepsis-induced immunosuppression in two mouse models of fungal sepsis. METHODS: Fungal sepsis was induced in mice using two different models of infection, that is, primary fungal sepsis and secondary fungal sepsis occurring after sub-lethal cecal ligation and puncture (CLP).Anti-PD-1 and anti-PD-L1 were administered 24 to 48 h after fungal infection and effects on survival, interferon gamma production, and MHC II expression were examined. RESULTS: Anti-PD-1 and anti-PD-L1 antibodies were highly effective at improving survival in primary and secondary fungal sepsis.Both antibodies reversed sepsis-induced suppression of interferon gamma and increased expression of MHC II on antigen presenting cells.Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a second negative co-stimulatory molecule that is up-regulated in sepsis and acts like PD-1 to suppress T cell function, also improved survival in fungal sepsis. CONCLUSIONS: Immuno-adjuvant therapy with anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies reverse sepsis-induced immunosuppression and improve survival in fungal sepsis.The present results are consistent with previous studies showing that blockade of PD-1 and CTLA-4 improves survival in bacterial sepsis.Thus, immuno-adjuvant therapy represents a novel approach to sepsis and may have broad applicability in the disorder.Given the relative safety of anti-PD-1 antibody in cancer clinical trials to date, therapy with anti-PD-1 in patients with life-threatening sepsis who have demonstrable immunosuppression should be strongly considered.