# Serum AGP-1-Lex Glycoforms Report on Survivorship of Patients with Septic Shock Upon Admission to Intensive Care Unit

## TL;DR

This study identifies specific sugar molecules in blood that can predict survival chances of septic shock patients when they enter the ICU.

## Contribution

The study introduces AGP-1-Lex glycoforms as a novel biomarker for early risk stratification of septic shock patients.

## Key findings

- AGP-1-Lex glycoforms are elevated in nonsurvivors of septic shock at ICU admission.
- A machine learning model using glycome data achieved 94.6% accuracy in predicting patient outcomes.
- AGP-1 is identified as a key carrier of Lex glycoepitopes associated with septic shock survival.

## Abstract

Septic shock, the excessive immune response to pathogen infection, accounts globally for ∼20% of all deaths. Current methods to establish disease severity are unacceptably slow, unspecific, and insensitive, hindering timely and effective treatment. Aiming to establish easy-to-measure glyco-signatures that may identify the most critically unwell patients, we applied comparative glycomics and glycoproteomics to sera longitudinally collected from septic shock survivors (n = 29) and nonsurvivors (n = 8). Glycomics of all 134 serum samples (sampled daily until recovery/death) revealed significant N-glycome dynamics across both patient groups. Unsupervised clustering of the serum N-glycome measured upon intensive care unit (ICU) admission (day 1) indicated survivorship-specific glyco-signatures. We therefore employed machine learning to train a random forest model using the serum N-glycome data. The model accurately classified survivorship outcomes of 35 of 37 patients (accuracy 94.6%) and correctly predicted 29 of 29 survivors (specificity 100%) and six of eight nonsurvivors (sensitivity 75%). Interrogation of the serum N-glycome data revealed that Lewis x (Lex)-type N-glycans are elevated in nonsurvivors relative to survivors at ICU admission, a finding recapitulated by glycoproteomics. Among the 58 other Lex-containing serum glycoproteins that were strongly associated with acute phase response and stress pathways, alpha-1-acid-glycoprotein (AGP-1) was identified as a principal carrier of Lex glycoepitopes with a potential to stratify septic shock survivors from nonsurvivors (AUC 0.90). This study lays a foundation for risk stratification of septic shock patients by uncovering easy-to-assay AGP-1-Lex glycoforms that identify individuals experiencing poor survival outcomes already upon ICU admission, with the potential to translate to early individualized clinical care at the bedside.

Deep and temporal glycoproteome profiling of septic shock sera using multi-omics and ML approaches reveals that α-1-acid glycoprotein-Lex glycoforms stratify patient outcome upon ICU admission.

Deep and temporal glycoproteome profiling of septic shock sera using multi-omics and ML approaches reveals that α-1-acid glycoprotein-Lex glycoforms stratify patient outcome upon ICU admission.

•Deep and temporal N-glycoproteome profiling of septic shock sera using multi-omics.•Glycomics-trained ML model identifies septic shock survivors from nonsurvivors.•Lewis x (Lex)-type glycoepitopes are raised early in fatal septic shock.•α-1-acid glycoprotein-Lex glycoforms stratify patient outcome upon ICU admission.

Deep and temporal N-glycoproteome profiling of septic shock sera using multi-omics.

Glycomics-trained ML model identifies septic shock survivors from nonsurvivors.

Lewis x (Lex)-type glycoepitopes are raised early in fatal septic shock.

α-1-acid glycoprotein-Lex glycoforms stratify patient outcome upon ICU admission.

Septic shock lacks rapid prognostic markers. To tackle this clinical gap, this study performed comprehensive glycoproteome profiling of sera longitudinally collected from septic shock survivors and nonsurvivors using glycomics and glycoproteomics. Enabled by machine learning and deep data analysis, Lewis x glycoepitopes carried by alpha-1-acid glycoprotein were found to be elevated in fatal septic shock relative to disease survivors upon ICU admission. Our work indicates that specific glycoforms have prognostic value thereby supporting the precision management of septic shock patients.