Association between B and T lymphocyte attenuator/herpes virus entry mediator immunoregulatory axis and outcome prediction in a mixed critically ill population

Abstract B and T lymphocyte attenuator (BTLA) and herpes virus entry mediator (HVEM) are emerging immune checkpoint molecules implicated in immune dysregulation during critical illness. We investigated the prognostic relevance of baseline serum soluble BTLA (sBTLA) levels and neutrophil HVEM mRNA expression, as well as their trajectories in critically ill patients. We analyzed 85 patients of a general ICU and measured the biomarkers at four time points. A control group of healthy volunteers (n = 25) was also included. Associations with ICU mortality were assessed using Cox regression, receiver operating characteristic-area under curve (ROC-AUC) analysis, and Kaplan-Meier survival analysis. We also used principal component analysis (PCA), linear mixed-effects models (LMEMs) and latent class mixed modeling (LCMM). Baseline sBTLA correlated positively with inflammatory, immunosuppression and clinical severity markers, including IL-6, IL-10, CRP, lactate, APACHE II, and SOFA scores. PCA identified sBTLA as the strongest contributor to the principal severity axis (loading = 0.29). ROC-AUC for sBTLA predicting ICU mortality was 0.714 (p = 0.003), while higher sBTLA tertiles were associated with increased ICU mortality (Log rank p = 0.01). In a multivariable Cox regression, baseline sBTLA levels were associated with increased ICU mortality (HR = 1.09, 95% CI = 1.01–1.18, p = 0.02). In a multivariable LMEM, ICU outcome had a strong overall effect (β = 2.58, p < 0.001), with non-survivors showing higher sBTLA values across the observation period. LCMM identified two trajectory classes; Class 1 (15.3%) had higher baseline sBTLA and increased ICU mortality risk (OR = 3.7, p = 0.03). Neutrophil HVEM mRNA expression was lower in ICU patients than in healthy controls, but showed no association with survival or other clinical variables. It demonstrated no predictive value for ICU outcomes. Both baseline and increasing sBTLA levels over time were associated with ICU mortality. sBTLA may serve as a dynamic biomarker of immune dysregulation and adverse outcomes.