PD-L1 and the risk of bacterial infection in patients with chronic liver diseases: An international multicohort study

Abstract

Bacterial infection; Biomarkers; Decompensated cirrhosis

Infección bacteriana; Biomarcadores; Cirrosis descompensada

Infecció bacteriana; Biomarcadors; Cirrosi descompensada

Background & Aims Impaired phagocytic capacity due to activation of the PD-1/PD-L1 pathway has been implicated in the development of bacterial infections in patients with cirrhosis. Soluble PD-L1 (sPD-L1) is easily measurable in plasma and has been proposed as a biomarker of sepsis. In the current study, we aim to evaluate the role of sPD-L1 as a biomarker of bacterial infection development in patients with cirrhosis. Methods Plasma samples from 995 patients with chronic liver disease grouped in three cohorts were analyzed: an initial cohort of 268 hospitalized patients with acute decompensated cirrhosis, 327 out-patients with non-acute decompensated cirrhosis and finally 400 patients with high-risk alcohol consumption, including all stages of liver fibrosis, from mild/no fibrosis to cirrhosis (F0–F4). The main outcomes of the study were development of bacterial infection and mortality. Results Patients who developed bacterial infections had higher median levels of sPD-L1 than those who did not (160 [IQR 116-221] vs. 136 [IQR 97-193] pg/ml, respectively, p value <0.001; hazard ratio 1.034, 95% CI 1.014-1.055). Levels of sPD-L1 were associated with bacterial infection development after adjustment for confounding factors. During follow-up, patients who died had higher median sPD-L1 levels than survivors, after adjustment for MELD Na (180 [IQR 143-267] vs. 134 [IQR 97-187] pg/ml, respectively; p value <0.001; HR 1.066, 95% CI 1.043-1.089). These findings were observed in all cohorts. Conclusions Plasma levels of sPD-L1 are associated with the risk of bacterial infection development irrespective of the stage of chronic liver disease. Furthermore, higher sPD-L1 levels are linked to increased mortality. Measurement of sPD-L1 levels may help identify patients at high risk of developing bacterial infections and guide the implementation of new preventive strategies. Impact and implications This study explores the role of soluble PD-L1 as a biomarker of immune dysfunction and its association with clinical outcomes in patients with chronic liver disease. Our findings demonstrate that soluble PD-L1 levels increase with the progression of liver disease and they are independently associated with an increased risk of bacterial infection development and mortality. These results could help physicians identify high-risk individuals earlier and implement preventive strategies.

This work was supported by a grant awarded to PG (PI23/00798), integrated in the Plan Nacional I+D+I, and co-funded by ISCIII-Subdirección General de Evaluación and European Regional Development Fund. AJ has been supported by a grant funded by Instituto de Salud Carlos III (PI24/01100). EP has been supported by a grant funded by Instituto de Salud Carlos III (PI22/00910). MJM has been funded by Contracte de Recerca “Clínic - La Pedrera”, granted by Hospital Clínic de Barcelona. SP has been supported by a grant from the Italian Ministry of Health (GR-2021-12374075). AS is co-financed by a Río Hortega grant and the European Union (expediente CM23/00133), Instituto de Salud Carlos III, Acción Estratégica en Salud, December 2023 Call. IG has been supported by a grant funded by Instituto de Salud Carlos III (PI22/00776). AC is funded by the Instituto de Salud Carlos III (ICSIII) through the project PI19/00752 and co-funded by the European Union. MT is funded by a grant from the Novo Nordisk Foundation (NNF20OC0059393). TH is funded by Novo Nordisk Foundation (grant no. NNF15OC0016544), the Novo Nordisk Foundation Challenge Program (grant no. NNF15OC0016692) and to the MicrobLiver consortium.