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Dual Reporting of Clostridioides difficile PCR and Predicted Toxin Result Based on PCR Cycle Threshold Reduces Treatment of Toxin-Negative Patients without Increases in Adverse Outcomes.

ABSTRACT: Nucleic acid amplification tests are commonly used to diagnose Clostridioides difficile infection (CDI). Two-step testing with a toxin enzyme immunoassay is recommended to discriminate between infection and colonization but requires additional resources. Prior studies showed that PCR cycle threshold (C_T ) can predict toxin positivity with high negative predictive value. Starting in October 2016, the predicted toxin result (CT-toxin) based on a validated cutoff was routinely reported at our facility. To evaluate the clinical efficacy of this reporting, all adult patients with positive GeneXpert PCR results from October 2016 through October 2017 underwent a chart review to measure the recurrence of or conversion to a CT-toxin⁺ result and 30-day all-cause mortality. There were 482 positive PCR tests in 430 unique patients, 282 CT-toxin⁺ and 200 CT-toxin^- Patient characteristics were similar at testing, though CT-toxin⁺ patients had higher white blood cell (WBC) counts (12.5 × 10³ versus 9.3 × 10³ cells/μl; P = 0.001). All cases (n = 21) of fulminant CDI had a CT-toxin⁺ result. Index CT-toxin⁺ patients were significantly more likely to have a CT-toxin⁺ result within 90 days than CT-toxin^- patients (17.4% [n = 49] versus 8.0% [n = 16], respectively; P = 0.003). Thirty-day all-cause mortality was higher in CT-toxin^- patients (11.1% versus 6.8%; P = 0.1), though no deaths in CT-toxin^- patients were directly attributable to CDI. Of the 200 CT-toxin^- patients, 51.5% (n = 103) were treated for CDI. The rates of conversion to a CT-toxin⁺ result (8.8% versus 7.2%; P = 0.8) and all-cause mortality (8.8% versus 13.4%; P = 0.3) were similar between treated and untreated CT-toxin^- patients, respectively. C_T -based toxin prediction may identify patients at higher risk for CDI-related complications and reduce treatment among CT-toxin^- patients.

SUBMITTER: Hitchcock MM

PROVIDER: S-EPMC6812995 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The anaerobic spore former Clostridioides difficile causes significant diarrheal disease in humans and other mammals. Infection begins with the ingestion of dormant spores, which subsequently germinate within the host gastrointestinal tract. There, the vegetative cells proliferate and secrete two exotoxins, TcdA and TcdB, which cause disease symptoms. Although spore formation and toxin production are critical for C. difficile pathogenesis, the regulatory links between these two physiological processes are not well understood and are strain dependent. Previously, we identified a conserved C. difficile regulator, RstA, that promotes sporulation initiation through an unknown mechanism and directly and indirectly represses toxin and motility gene transcription in the historical isolate 630Δerm To test whether perceived strain-dependent differences in toxin production and sporulation are mediated by RstA, we created an rstA mutant in the epidemic ribotype 027 strain R20291. RstA affected sporulation and toxin gene expression similarly but more robustly in R20291 than in 630Δerm In contrast, no effect on motility gene expression was observed in R20291. Reporter assays measuring transcriptional regulation of tcdR, the sigma factor gene essential for toxin gene expression, identified sequence-dependent effects influencing repression by RstA and CodY, a global nutritional sensor, in four diverse C. difficile strains. Finally, sequence- and strain-dependent differences were evident in RstA negative autoregulation of rstA transcription. Altogether, our data suggest that strain-dependent differences in RstA regulation contribute to the sporulation and toxin phenotypes observed in R20291. Our data establish RstA as an important regulator of C. difficile virulence traits.IMPORTANCE Two critical traits of Clostridioides difficile pathogenesis are toxin production, which causes disease symptoms, and spore formation, which permits survival outside the gastrointestinal tract. The multifunctional regulator RstA promotes sporulation and prevents toxin production in the historical strain 630Δerm Here, we show that RstA exhibits stronger effects on these phenotypes in an epidemic isolate, R20291, and additional strain-specific effects on toxin and rstA expression are evident. Our data demonstrate that sequence-specific differences within the promoter for the toxin regulator TcdR contribute to the regulation of toxin production by RstA and CodY. These sequence differences account for some of the variability in toxin production among isolates and may allow strains to differentially control toxin production in response to a variety of signals.

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Dual Reporting of Clostridioides difficile PCR and Predicted Toxin Result Based on PCR Cycle Threshold Reduces Treatment of Toxin-Negative Patients without Increases in Adverse Outcomes.

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