Neurological manifestations and MMP8 as a prognostic biomarker in severe fever with thrombocytopenia syndrome

by Qi Xia, Ziling Cheng, Yi Zhang, Haolin Song, Bei Jia, Lingtong Huang, Qiuhong Liu, Qing Zhao, Jie Li, Jie Wang, Wei Wu

Background

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality. Neurological symptoms are increasingly recognized as critical predictors of poor outcomevs, but their mechanisms remain unclear. This study aims to explore relevant mechanisms and identify biomarkers.

Methods

This study utilized three distinct SFTS patient cohorts. First, 15 hospitalized patients from April 21 to August 2, 2024 were prospectively enrolled, with blood samples collected during hospitalization for RNA sequencing of peripheral blood mononuclear cells (PBMCs) to identify differentially expressed genes (DEGs). Second, we established a single-center retrospective cohort comprising 103 SFTS patients (admitted 2021–2024) to analyze clinical data pertaining to central nervous system (CNS) symptoms and patient outcomes. Third, to quantitatively assess serum matrix metalloproteinase-8 (MMP8) levels, we analyzed a total of 151 serum samples obtained from patients across two independent centers using enzyme-linked immunosorbent assay (ELISA).

Results

RNA sequencing analysis between the recovered group and deceased group revealed significant alterations in central nervous system (CNS)-related pathways. Clinical data from 103 SFTS patients showed the deceased group had significantly higher rates of neurological symptoms vs the recovered group over the full course: consciousness disorders (88.89% vs 23.53%, P < 0.001) and convulsions (27.78% vs 3.53%, P = 0.003). Patients with these symptoms had both upregulated MMP8 gene expression and elevated serum MMP8 levels. Elevated serum MMP8 strongly correlated with fatal outcomes (AUC = 0.821, 95% CI: 0.681-0.962; P = 0.008). Multivariate Cox analysis confirmed MMP8 as an independent mortality predictor (HR = 1.060, 95% CI: 1.010-1.112). The MMP8-incorporated multivariable Cox model showed good discriminative ability in the external validation cohort (AUC = 0.843, 95% CI: 0.723-0.962).

Conclusions

Neurological symptoms during the early stages of SFTS are strongly associated with patient outcomes. MMP8 may serve as a potential biomarker for SFTS prognosis. The integration of clinical neurological symptoms and MMP8 measurement offers a novel framework for improving prognostic accuracy and guiding personalized management strategies in SFTS patients.