Natural History of Clostridioides difficile-related Disease Progression in the Two-Step Testing Era

Abstract Importance The natural history of C. difficile progression in nucleic acid amplification test (NAAT) positive, toxin enzyme immunoassay-negative patients remains poorly described. Better understanding risk for subsequent disease may improve prevention strategies. Objective Describe the natural history of C. difficile NAAT+/toxin- adults. Design A cohort of adults (≥18 years) tested for C. difficile within Duke University Health System between 15 March 2020 and 31 December 2023 were classified as NAAT-, NAAT+/toxin-, or NAAT+/toxin+ and followed up to 90 days. Three time-to-event analyses were conducted. Incidence of toxin+ episodes was assessed by initial test status (analysis 1). Treatment of NAAT+/toxin- adults was described using cumulative incidence curves (analysis 2). Rates of toxin+ episodes and severe disease were compared between treated and untreated NAAT+/toxin- adults (analysis 3). Results The cohort included 24,474 tests and 440 toxin+ episodes among 18,337 unique subjects followed for a median 71 days. NAAT+/toxin- status was associated with subsequent toxin positivity (adjusted hazard ratio, aHR 5.06, 95% CI 3.61-7.10) – especially after antibiotic receipt (aHR 15.71, 95% CI 9.85-25.06). Among 2,334 NAAT+/toxin- episodes, 33% received presumptive treatment. Just 5% of NAAT+/toxin- subjects progressed to toxin positivity. Presumptive treatment was associated with lower hazard of subsequent toxin positivity (aHR 0.12, 95% CI 0.05-0.29) but not fulminant disease (aHR 1.93, 95% CI 0.50-7.45). Conclusions and Relevance C. difficile NAAT+/toxin- status was associated with subsequent toxin positivity, especially after antibiotic receipt, though absolute risk was low overall. Further research is needed to determine whether and for whom presumptive treatment might be beneficial.