Circulating cell-death-associated biomarkers and inflammatory severity in Hymenoptera sting envenomation: a single-center retrospective study

Severe Hymenoptera sting envenomation can cause systemic inflammation, shock, and multi-organ injury. Gasdermin D cleavage and RIPK3 phosphorylation are associated with inflammatory cell-death pathways, but circulating measurements cannot by themselves establish a specific cellular death mechanism. We therefore evaluated the clinical associations of serum GSDMD-p30, p-RIPK3, IL-1β, and IL-18 with illness severity in patients with Hymenoptera sting envenomation.

We conducted a single-center retrospective study of 142 adults admitted between January 2023 and December 2025. Clinical severity was categorized at admission using a four-level institution-specific scheme: Grade I, local/minimal systemic manifestations without organ dysfunction; Grade II, systemic allergic manifestations without organ dysfunction; Grade III, single-organ failure; and Grade IV, multi-organ failure and/or anaphylactic shock. Archived serum was available for 98 patients (Grade I/II/III/IV: 30/33/22/13). Serum GSDMD-p30, p-RIPK3, IL-1β, and IL-18 were measured by ELISA-based assays. Associations with severity grade and SOFA score and exploratory same-cohort ROC performance for Grade III-IV disease were assessed.

The cohort included 42 Grade I, 48 Grade II, 34 Grade III, and 18 Grade IV patients. Sting count, time to hospital presentation, inflammatory indices, organ-injury markers, SOFA score, ICU admission, and length of stay increased with clinical severity. In the serum subset, mean GSDMD-p30 increased from 0.82 ± 0.21 ng/mL in Grade I to 9.43 ± 2.18 ng/mL in Grade IV, and p-RIPK3 increased from 0.64 ± 0.18 to 7.84 ± 1.87 ng/mL (global p < 0.001 for both). IL-1β and IL-18 showed similar severity-associated increases. Correlations with SOFA score were ρ = 0.814 for GSDMD-p30, ρ = 0.783 for p-RIPK3, ρ = 0.791 for IL-18, and ρ = 0.762 for IL-1β (all p < 0.001). Apparent AUCs for Grade III-IV disease were 0.861, 0.843, 0.834, and 0.812, respectively.

Circulating GSDMD-p30, p-RIPK3, IL-1β, and IL-18 were associated with clinical severity and organ-failure burden in this retrospective cohort. These findings support further evaluation of these proteins as candidate severity-associated biomarkers, but they do not demonstrate PANoptosis, establish cell-specific origin, or validate a clinical triage tool. Prospective multicenter studies with standardized assays and adjusted analyses are required.