Use of Dynamic Soluble Programmed Death-Ligand 1 Trajectories to Identify Early Organ Dysfunction and Predict Mortality in Critical Coronavirus Disease 2019

Background Persistent immune checkpoint activation is a recognized feature of critical Coronavirus Disease 2019 (COVID-19). However, the temporal behavior and clinical utility of soluble Programmed Death-Ligand 1 (sPD-L1) remain unclear. We aimed to investigate the longitudinal changes in sPD-L1, their relationship with organ dysfunction markers, and their prognostic value when combined with machine learning (ML) models. Methods This single-center observational study included 40 adults with severe COVID-19 pneumonia admitted to the intensive care units (ICU) (April 2021–December 2022) and 23 healthy volunteers. We measured plasma sPD-L1 on ICU days 1, 5, 7, 14, and 21. Routine biochemistry, full blood counts, and arterial blood gas analyses were conducted in parallel. Cox regression analysis was used to identify independent predictors of hospital mortality, which was the primary outcome. Eight ML classifiers were trained on admission variables, as well as day 1, 5, and 7 sPD-L1 levels. Discrimination was assessed using stratified five-fold cross-validation and Shapley Additive Explanations (SHAP) attribution. Results Ten of the forty patients died during hospitalization. Overall, sPD-L1 levels declined during the ICU stay but remained persistently high in non-survivors. Values on days 5 and 7 differed significantly between survivors and non-survivors (p = 0.023 and 0.001, respectively). In multivariable Cox analysis, day-7 sPD-L1 and arterial lactate levels on admission independently predicted mortality. Day 7 sPD-L1 level correlated positively with creatinine, C-reactive protein, and fibrinogen (all p < 0.05), linking immune checkpoint activation to renal injury, inflammation, and coagulopathy. A support vector machine model achieved the highest discriminative accuracy (mean area under the curve = 0.917). Day 5 sPD-L1 was designated as the primary predictor of mortality based on SHAP attribution, with lactate contributing minimally. Conclusion Sustained sPD-L1 elevation in the initial ICU week is strongly associated with early organ dysfunction and independently predicts death in critical COVID-19. Incorporating serial sPD-L1 levels into bedside ML models significantly enhances risk discrimination. These findings support sPD-L1 as an integrative biomarker of immune–renal–coagulation interplay, thus necessitating validation in larger multicenter cohorts and exploration as a potential companion marker for immune-modulatory interventions.