Sepsis associated with Clostridioides difficile infection carries similar mortality to sepsis of other origin: a propensity score-matched analysis.

Severe Clostridioides difficile infection (CDI) is associated with high mortality, partly due to comorbidities. We aimed to assess whether sepsis due to CDI leads to worse outcomes compared to sepsis from other infections and whether CDI is associated with a distinct host immune profile. In this retrospective analysis, patients with CDI and sepsis, included in two prospective multi-center CDI studies, (one conducted during 2015-2021 and one during 2022-2023), were compared to comorbidity- and severity-matched patients with sepsis of other cause [community acquired pneumonia (CAP), hospital-acquired or ventilator-associated pneumonia (HAP/VAP), intra-abdominal infection (IAI), and primary bloodstream infection (BSI)], enrolled in a National prospective sepsis registry (during 2006-2024). The primary outcome was 28-day mortality. Baseline inflammatory biomarkers were compared among groups. We analyzed 549 patients, 132 with CDI, matched with 128 patients with CAP, 74 with HAP/VAP, 117 with IAI, and 98 with BSI. Mortality in CDI was 28.8%, similar to non-CDI sepsis (27.1%, OR 1.09, 95% CI 0.70-1.68; P = 0.705) and to each of the four infection subgroups. CDI patients displayed higher calprotectin stool excretion than non-CDI comparators (excretion ratio 4.53 vs. 1.99; p = 0.005). CDI-associated sepsis has similar mortality to sepsis of other origin. Calprotectin may be a key inflammatory mediator.