A Reproducible Ceramide Phenotype of Sepsis Across Aetiologies - A Monocenter Cohort Study

Sepsis due to SARS-CoV-2 shares features with non-COVID-19 sepsis. Ceramides-bioactive sphingolipids-exist as long-chain (LC) and very-long-chain (VLC) species with opposing signaling effects. Whether LC and VLC ceramides are altered similarly in COVID-19 vs non-COVID-19 sepsis, and the therapeutic relevance of sphingomyelinase inhibition, remains uncertain. We characterised circulating ceramides in patients with systemic inflammatory response syndrome (SIRS) or sepsis with and without SARS-CoV-2.

We performed targeted lipidomics on serum/plasma in two cohorts: (i) plasma from 157 SIRS/sepsis patients with different disease etiologies, including 23 patients with SARS-CoV-2 and 23 healthy controls; (ii) serum from 96 SIRS/sepsis patients with SARS-CoV-2 and 17 patients without SIRS/sepsis and without SARS-CoV-2. We quantified individual ceramide species in the serum or plasma of patients and controls simultaneously. The ceramide species levels of patients and controls, as well as patients with and without SARS-CoV-2, were compared. In the patients we assessed associations with C-reactive protein, cholesterol, and survival.

Relative to non-septic comparators, SIRS/sepsis showed higher ceramide 18:1;O2/16:0, 18:0, 20:0, and 24:1 (p < 0.001 for all), and lower ceramide 18:1;O2/23:0, 24:0 (p = 0.001 for both), and 26:0 (p < 0.001). Ceramide profiles were comparable between SARS-CoV-2 and non-SARS-CoV-2 sepsis (p > 0.05). Several ceramides correlated positively with C-reactive protein and cholesterol, yet these variables did not account for the divergent regulation of LC (increased) versus VLC (mostly decreased) species. Neither individual ceramides nor the LC/VLC ratio was associated with survival (p > 0.05).

Sepsis is characterised by a reproducible ceramide signature that does not differ by SARS-CoV-2 status. These data argue against non-selective acid sphingomyelinase inhibition and instead support evaluation of selective ceramide synthase targeting as a therapeutic approach in sepsis.