Are Certain Strains of C Diff Associated With Higher All-Cause Mortality Risks?

Clostridium difficile (C diff) is estimated to occur in approximately 500,000 individuals each year in the United States, according to the US Centers for Disease Control and Prevention. The burden of the infection is considerable, with 1 in 11 people over the age of 65 dying within a month of a health care-associated C diff diagnosis.

Yet conflicting information is reported across studies evaluating the link between different bacterial strains of C diff and the risk of mortality associated with the infection.

To explore this link, investigators from the Department of Microbiology and Infectious Disease at the University of Sherbrooke, in Sherbrooke, Canada, performed a meta-analysis of available literature, focusing on the strains NAP1/BI/027 and R027.

“We show in our review several reasons that could explain discrepancies between studies on the association of strain type and clinical outcomes including mortality,” the investigators, led by Claire Nour Abou Chakra, PhD, a research coordinator, told Contagion®. “The definition of the outcome varied widely across studies, using follow-up duration for mortality between three days and up to 12 months. Mortality could be directly attributable to C. difficile infection (CDI) or all-cause.”

The results of the literature review were presented in an oral abstract session at the European Congress for Clinical Microbiology and Infectious Diseases (ECCMID 2019).

“The review allowed us to gather all these studies and then stratify the findings in order to show the effect of these factors on the association of strains with clinical outcomes,” the authors said.

For the literature review, the investigators conducted a search, including all studies reporting mortality based on the bacterial strain type of C diff available on PubMed/MEDLINE, Cochrane Library, Embase, and Web of Sciences up to March 2018.

From there, the investigators performed a random effect meta-analysis to determine the frequency of mortality and risk ratio (RR). In total, 45 studies were included in the analysis and 30-day all-cause mortality was found to be the most frequent outcome.

The investigators found that 30-day attributable and all-cause mortality was higher in patients who were infected by R027 strain (pooled RR= 2.1; 95% Confidence Interval [CI] 1.3-3.4 and RR=1.6; 95%CI 1.1-2.3) but not 14-day all-cause mortality (RR=2.3; 95%CI 0.5-10.9).

“Whether it is 14-day or 30-day, the outcome remains all-cause death in usually elderly populations,” the investigators told Contagion®.

The analysis also revealed that the strain R078 was infrequent, with 30-day mortality not reported in patients with that particular strain in 3 studies. Overall, the association with the R078 strain was not significant (RR=0.9; 95%CI 0.4-2.1).

The investigators noted that the “risk of 30-day all-cause mortality was of 1.7 (95%CI 0.99-2.8) in patients infected by strains producing binary toxin.”

“Our main findings were that observed proportion of 30-day all-cause mortality was up to 23% in patients infected by four of the following strains: R001, R002, NAP1/R027, and R106. This proportion was lower when CDI was attributed to R014, R053, and R078 (9% to 13%). However, the risk of 30-day all-cause mortality was only higher with R001, R027, and with the strains harbouring the binary toxin gene,” the authors explained to Contagion®.

The results of the analysis lead the investigators to conclude that some strains in particular are likely associated with mortality in C diff infection, specifically, NAP1/BI/R027; however, attributable mortality is low (8%). For strains producing binary toxin, the association with all-cause mortality was reported to be “almost statistically significant.”

“Sensitivity analysis and meta-regression are needed to adjust these results on other factors mainly patients’ characteristics and underlying comorbidities,” the investigators noted.

“So far, we assessed this association overall and stratified according to criteria such as regions, studies ‘population (hospitalized only vs all CDI cases), or when data were collected (before and after outbreaks). However, the risk of mortality could not be fully attributable to a strain without taking into account other factors such as patients’ age, underlying comorbidities, or immune status. We are conducting meta-regressions using these factors in addition to strain types,” the authors concluded to Contagion®, indicating that more results are to come.

The study, “The relationship between strain type and mortality in Clostridioides difficile infection: a meta-analysis,” was presented in an oral abstract presentation on April 13, 2019, at ECCMID 2019 in Amsterdam, the Netherlands.