# Endotoxemia and its association with immune and coagulopathy responses in severe community-acquired pneumonia and COVID-19

## TL;DR

This study found no evidence of increased gut-derived endotoxemia in severe pneumonia or COVID-19 patients, challenging its role in systemic inflammation.

## Contribution

A highly specific mass spectrometry method revealed no elevated lipopolysaccharide in severe pneumonia or COVID-19 patients.

## Key findings

- Median plasma LPS concentrations were significantly lower in severe pneumonia and COVID-19 patients compared to healthy volunteers.
- LPS levels did not correlate with disease severity or mortality and showed no increased risk of thrombotic events.
- Findings challenge the hypothesis that gut-derived endotoxemia drives systemic inflammation in severe pneumonia.

## Abstract

Acute community-acquired pneumonia (CAP) is a leading cause of infection-related mortality worldwide. Endotoxemia, characterized by elevated plasma lipopolysaccharide (LPS), is a key driver of inflammation and thrombosis in Gram-negative sepsis and has been suggested to occur in severe pneumonia, irrespective of etiology. However, current immunoassays for LPS quantification lack sensitivity and specificity. We aimed to quantify plasma LPS in severe CAP patients, including COVID-19, using a validated mass spectrometry method, and to explore associations with immune activation, coagulation, gut translocation, and clinical outcomes.

In this prospective ancillary study of the LYMPHONIE cohort, we included 34 non-COVID-19 severe CAP (sCAP), 34 severe COVID-19 (sCOVID-19) and 34 matched healthy volunteers. Plasma LPS was measured by LC–MS/MS detecting 3-hydroxy fatty acids of lipid A. Clinical data, immune biomarkers, coagulation biomarkers, and gut injury markers were measured.

Unexpectedly, median plasma LPS concentrations were significantly lower in sCAP patients (724 pmol/ml in sCAP; 750 pmol/ml in sCOVID-19) compared to healthy volunteers (1009 pmol/ml, p < 0.001). LPS levels did not correlate with severity scores or mortality. Low positive correlations were observed between LPS and markers of endothelial activation (sVCAM-1) and coagulation (D-dimer). However, patients with high LPS showed no increased risk of thrombotic or cardiovascular events.

Using a highly specific LC–MS/MS method, we found no evidence of increased circulating LPS in severe pneumonia patients, challenging the hypothesis of gut-derived endotoxemia as a major contributor to systemic inflammation in severe CAP, including COVID-19.

Take-home message Using a highly specific mass-spectrometry assay, we found no evidence of elevated circulating lipopolysaccharide in severe community-acquired pneumonia, including COVID-19. These findings challenge the concept that gut-derived endotoxemia is a major driver of systemic inflammation in severe pneumonia.

Tweet Mass spectrometry reveals no rise in plasma LPS in severe pneumonia or COVID-19, questioning gut endotoxemia’s role in inflammation.

The online version contains supplementary material available at 10.1186/s40635-026-00863-y.