Circulating granzyme A is elevated within the dysregulated host response and associates with mortality in abdominal sepsis.

Abstract

Granzyme A (GzmA) has been identified as a key amplifier of sepsis-related inflammation in experimental models without contributing to pathogen clearance. However, its behavior and clinical relevance in human bacterial sepsis remain unknown. We aimed to characterize circulating GzmA in secondary peritonitis and explore its associations with clinical severity and all-cause mortality. We conducted a single-center prospective cohort study of 42 adults with secondary peritonitis at Lozano Blesa Clinical Hospital (Zaragoza, Spain), with 31 healthy controls. Peripheral blood was obtained at baseline, 24 h, and 48 h. Serum GzmA concentration and activity, GzmB, cytokines, and endothelial and coagulation markers were measured. Analyses included comparisons across Sepsis-3 severity strata and exploratory prognostic models (logistic regression and receiver operating characteristic curves) evaluating associations between baseline biomarkers and mortality. Sensitivity analyses were performed after excluding patients meeting predefined immunosuppression criteria. At baseline, GzmA concentrations (2.3-fold, q-value = 5.41×10 -12 ) and GzmA enzymatic activity (q-value = 6.75 × 10 - ³) were significantly higher in patients than controls, whereas GzmB did not differ (q-value = 0.332). Across baseline severity categories, VCAM-1 showed the clearest gradient (q-value = 0.017), while GzmA concentrations were numerically highest in septic shock (median 165.4 pg/mL). GzmA remained elevated through 48 h, and non-survivors had higher baseline levels than survivors. Each doubling of baseline GzmA was associated with higher overall in-hospital mortality (OR 2.52; 95% CI 1.11-5.75, p=0.028), with associations persisting after adjustment for age and comorbidity. Sensitivity analyses excluding immunosuppressed patients yielded a clearer association between GzmA and baseline severity, and confirmed its association with mortality. Circulating GzmA, but not GzmB, is markedly upregulated, remains elevated during early follow-up, and is preliminarily associated with mortality-related outcomes. These exploratory findings are consistent with experimental models and support further evaluations of extracellular GzmA to investigate its biological and potential translational relevance in sepsis.