The High-Sensitivity C-reactive Protein-to-High-Density Lipoprotein Cholesterol Ratio (HCHR) as a Novel Composite Biomarker for Predicting 28-day All-cause Mortality in Sepsis: a Retrospective Cohort Study

Abstract

Background: Sepsis remains a leading cause of critical illness and mortality, and early risk stratification relies on biomarkers with variable performance. High inflammatory activity and dysregulated lipid metabolism are central features of sepsis, yet the prognostic value of composite inflammatory-metabolic biomarkers remains insufficiently clarified. The high-sensitivity C-reactive protein-to-high-density lipoprotein cholesterol ratio (hs-CRP/HDL-C ratio, HCHR) has been proposed as a novel composite biomarker. HCHR integrates inflammatory and metabolic information, potentially offering superior prognostic insights. Methods: A total of 1069 patients with sepsis admitted to the ICU of Affiliated Jinhua Hospital, Zhejiang University School of Medicine between May 2015 and March 2025 were retrospectively enrolled. Patients were divided into quartiles based on HCHR. The primary outcome was 28-day all-cause mortality. Multivariable logistic regression (fully adjusted models) was conducted to assess the association between HCHR and 28-day mortality. Sensitivity analyses excluded lipid-related covariates (TG and LDL-C). Spearman's partial correlation was performed with pooling across imputations. Robustness was assessed through subgroup analysis and restricted cubic spline (RCS) modeling, while discrimination was evaluated using receiver operating characteristic (ROC) curves with DeLong tests. Internal validation of the fully adjusted model was conducted using 5-fold cross-validation and bootstrap optimism correction. Results: In the fully adjusted model, higher HCHR was independently associated with increased 28-day mortality (OR 6.10, 95% CI 3.48-10.68, P < 0.001). The association remained robust in sensitivity analyses excluding TG and LDL-C (OR 5.40, 95% CI 3.19-9.14). Subgroup analysis revealed a stronger association among patients aged ≥65 years and those with hypertension (P for interaction = 0.002 and 0.014, respectively). RCS modeling indicated a linear positive relationship between HCHR and 28-day mortality (P for non-linearity = 0.748). HCHR showed moderate discrimination for predicting 28-day mortality (AUC 0.686, 95% CI 0.651-0.722), outperforming hs-CRP and HDL-C alone. Conclusions: HCHR is independently associated with 28-day all-cause mortality in sepsis and demonstrates moderate discriminative performance. HCHR may serve as a useful adjunct biomarker to support early risk stratification in sepsis.