Persistent inflammation, immunosuppression, and catabolism are associated with impaired lymphocytic mitochondrial metabolism during the early phase of sepsis. A single-center, prospective cohort study.

BACKGROUND: Lymphopenia and lymphocytic metabolism have been individually associated with poor prognosis in sepsis; however, the relationship between these factors remains poorly understood. We evaluated whether lymphocyte count and lymphocytic mitochondrial metabolism are associated with the development of persistent inflammation, immunosuppression, and catabolic syndrome (PICS). METHODS: A prospective cohort study was conducted in four clinical-surgical intensive care units (ICUs). We included critically ill patients with sepsis requiring vasopressor support and assessed mitochondrial metabolism in isolated lymphocytes, including Complex I- and II-linked respiration, at sepsis diagnosis (day 1) and on day 3. Absolute lymphocyte counts and derived ratios, e.g., neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), were evaluated at the same time points. The primary outcome was the association between mitochondrial respiratory function and PICS. Secondary outcomes included associations between lymphocyte counts, derived biomarkers, and mitochondrial respiration. RESULTS: We included 64 patients, 10 of whom developed PICS. At sepsis diagnosis, patients who did not develop PICS exhibited significantly higher Complex I and II-linked respiration compared with those who did (mean difference [MD] for Complex I: 115 pmol O₂ s-1 10-6 cells; 95% CI: 13-291; P = 0.01; MD for Complex II: 171 pmol O₂ s-1 10-6 cells; 95% CI: 31-397; P = 0.01). No significant differences were observed in the delta (day 3 minus day 1) mitochondrial respiration or lymphocyte count between the PICS and non-PICS groups. Additionally, lymphocyte counts and derived ratios showed no significant correlation with Complex I or II respiration, even when stratified by quartiles across time points. CONCLUSIONS: Our findings suggest that reduced mitochondrial Complex I- and II-linked respiration in lymphocytes at sepsis onset may be associated with the development of PICS. Nevertheless, this association remains exploratory and requires confirmation in larger, adequately powered studies.