Genomic determination of relative risks for Clostridioides difficile infection from asymptomatic carriage in ICU patients

Background Clostridioides difficile infections (CDIs) are among the most prevalent hospital-associated infections (HAIs), particularly for intensive care unit (ICU) patients. The risks for developing active CDI from asymptomatic carriage of C. difficile are not well understood. Methods We identified asymptomatic C. difficile carriage among 1897 ICU patients, using rectal swabs from an existing ICU vancomycin-resistant Enterococci (VRE) surveillance program. C. difficile isolates from VRE swabs, and from C. difficile -positive stool samples, were genome sequenced to assess clonal relationships among isolates from asymptomatic carriers and CDI patients. Integrated genomic and epidemiologic analyses identified multiple cases of asymptomatic carriers who developed CDI, and of asymptomatic transmission of C. difficile to naïve patients. Results Genomic analyses identified diverse strains in infected patients and asymptomatic carriers. 7.4% of ICU patients asymptomatically carried C. difficile . 69% of isolates carried an intact toxin locus. In contrast, 96% of C. difficile stool isolates were toxigenic. CDI rates in asymptomatic carriers of toxigenic strains were 5.3%, versus 0.57% in non-carriers. The relative risk for CDI with asymptomatic carriage of a toxigenic strain was 9.32 (95% CI=3.25-26.7). Genomic identification of clonal clusters supported epidemiologic analyses for asymptomatic transmission events, with spatial-temporal overlaps identified in 13 of 28 cases. Conclusions Our studies provide the first genomically-confirmed assessments of CDI relative risk from asymptomatic carriage of toxigenic strains and highlight the complex dynamics of asymptomatic transmission in ICUs. C. difficile screening can be implemented within existing HAI surveillance programs and, with isolation of asymptomatic carriers, has potential to reduce these risks. Summary Relative risks for C. difficile infections rise to 9.32 in asymptomatic ICU patients carrying toxigenic strains. Integrated genomic and epidemiologic analyses illustrate functional use of C. difficile genomic data to identify asymptomatic transmission events and assist in outbreak investigations.