Efficiency of a Multi-step Screening and Enrichment Process for Prospective Sepsis Cohort Enrollment

Background: Host response and biomarker research to advance sepsis therapeutics requires well-characterized cohorts with longitudinal biospecimens across a range of hosts and infections. Automated screening based on SIRS criteria is sensitive but nonspecific and identifies more candidates than research teams can approach, sample, and follow longitudinally. We evaluated a structured enrichment review by non-physician study staff, done after automated screening in a hospital-wide prospective sepsis cohort. Methods: The CISID cohort is a prospective observational study of hospitalized patients with suspected sepsis, enrolling adults from the ED, inpatient wards, and ICUs at a tertiary academic medical center. Patients were identified through: (1) automated electronic health record screening for two or more SIRS criteria with a 24-hour lookback, documentation of microbiologic culture or PCR, and receipt of a new antibiotic; (2) a sepsis enrichment step of structured chart review by trained non-physician study staff; and (3) discussion with the primary clinical team. Enrolled patients underwent physician adjudication into four diagnostic categories. To evaluate the enrichment step, we analyzed all patients screened during a 9-week period, assigned a composite "sepsis-likely" variable (CDC Adult Sepsis Event criteria or ICD-10 code R65.20/R65.21 within 48 hours before or after screening), and assessed mortality across each stage of screening. We also assessed concordance of the composite with physician adjudication among enrolled patients. Results: From November 2023 through February 2026, 4,318 patients screened in through EHR-based automated screening; 1,220 (28%) were flagged for enrollment, and 288 were enrolled. Physician adjudication classified 209 (73%) as sepsis, 46 (16%) as infection without sepsis, 14 (5%) were classified as undifferentiated critical illness, and 19 (6.6%) as non-infectious sepsis mimics. Patients with sepsis were severely ill (median SOFA score, 9; ICU admission, 80%; shock, 48%), and 51% were immunocompromised; mortality was 14% in hospital and 27% at 90 days. In a 9-week sample of 907 screened encounters, 21% of those deferred and 70% of those flagged for enrollment met the sepsis-likely composite, a 3.3-fold increase in prevalence after structured study team review. Conclusions: A brief structured enrichment review after automated screening tripled the prevalence of EHR-based sepsis indicators among patients selected for enrollment, while concentrating enrollment efforts on roughly one-quarter of screened-in patients in this hospital-wide, all-source suspected-sepsis cohort. This approach may help prospective cohorts direct limited biospecimen resources toward patients most informative for host-response and biomarker research.