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

## TL;DR

This study finds that neurological symptoms and elevated MMP8 levels are linked to poor outcomes in SFTS patients, offering a potential biomarker for prognosis.

## Contribution

The study identifies MMP8 as a novel prognostic biomarker for severe fever with thrombocytopenia syndrome (SFTS) based on clinical and transcriptomic data.

## Key findings

- Neurological symptoms like consciousness disorders and convulsions are strongly associated with higher mortality in SFTS patients.
- Elevated serum MMP8 levels correlate with fatal outcomes and serve as an independent predictor of mortality.
- Integration of clinical symptoms and MMP8 measurements improves prognostic accuracy for SFTS.

## Abstract

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.

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).

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).

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.

This study investigates the relationship between severe fever with thrombocytopenia syndrome (SFTS) patients’ outcome, neurological symptoms, and transcriptome changes, addressing critical knowledge gaps in this emerging infectious disease. Patients were categorized into deceased group and recovered group based on their clinical outcomes. By comparing gene expression profiles and clinical neurological symptoms between these groups, we identified matrix metalloproteinase-8 (MMP8) as a potential biomarker for predicting poor prognosis in SFTS patients. Furthermore, our results indicated that among the various neurological manifestations in SFTS patients, the presence of consciousness disorder and convulsion may serve as markers of poor prognoses. These findings advance the understanding of the neurological and molecular factors underpinning SFTS. We aim to assist clinicians in identifying SFTS patients with poor prognosis early, and providing timely supportive treatment for these high-risk patients to improve their survival outcomes.