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Molecular testing without toxin immunoassay may overdiagnose C. difficile infection

A recent study demonstrated that the majority of complications and deaths related to Clostridium difficile infection in hospitalized patients occurred in those with positive toxin immunoassay test results, while those who were toxin immunoassay negative but polymerase chain reaction positive had similar outcomes to patients without C. difficile infection.

“Over the past several years there has been a movement nationally and around the world to change test methods for C. difficile diagnosis from traditional toxin tests to newer, molecular tests,” Christopher R. Polage, MD, associate professor of pathology and infectious diseases at University of California Davis Medical Center, said in a press release. “This has been driven by concern that patients with infections were being missed, but very few studies looked at clinical outcomes to see if these concerns were justified.”

Polage and colleagues performed a prospective observational cohort study involving 1,416 adults with suspected C. difficile infection who were hospitalized between December 1, 2010, and October 20, 2012, at the UC Davis Medical Center. All patients submitted diarrheal stool samples for C. difficile toxin testing at least 72 hours after admission, the results of which were reported clinically. Eligible stool samples were also submitted for at least one molecular C. difficile test, the results of which were not reported. Patients were then grouped for outcomes analyses based on toxin immunoassay results (Tox) and polymerase chain reaction (PCR) results: Tox+/PCR+ (9.3%), Tox–/PCR+ (11.4%), Tox+/PCR–, or Tox–/PCR– (79.3%).

Overall, 21% were PCR+, and of them, 44.7% were also Tox+. Tox–/PCR+ patients had lower C. difficile bacterial load and less antibiotic exposure, fecal inflammation and diarrhea compared with Tox+/PCR+ patients at baseline (all P < .001).

Tox–/PCR+ patients had shorter median diarrhea duration (2 days; IQR = 1-4 days) compared with Tox+/PCR+ patients (3 days; IQR = 1-6 days; P = .003), but comparable median diarrhea duration to Tox–/PCR– patients (2 days; IQR = 1-3 days).

“In the multivariable model, Tox+/PCR+ status had the strongest effect on duration of diarrhea, decreasing the probability of diarrhea being resolved by 37% each day relative to the Tox–/PCR– reference group (HR = 0.63; 95% CI, 0.48-0.83),” the researchers wrote.

C. difficile infection-related complications occurred in 7.6% of Tox+/PCR+ patients compared with none of the Tox–/PCR+ patients (P < .001), and C. difficile infection-related 30-day mortality occurred in 8.4% vs. 0.6%, respectively (P = .001).

“Up to half of the patients with positive molecular test results for C. difficile do not experience adverse events without treatment and do not need treatment for [C. difficile infection],” the researchers concluded. “Exclusive reliance on molecular tests for C. difficile diagnosis is likely to result in overdiagnosis, unnecessary treatment, and increased health care costs.”

“We found that virtually all of the bad, negative outcomes occurred in the patients with positive toxin tests,” Polage said in the press release. “This suggests that we should really focus on toxin-positive patients for treatment. There may be room for trying to improve the sensitivity of toxin tests and look for additional tests to help identify patients at greatest risk for bad outcomes. Apart from this, we need to understand that most toxin-negative patients don't need treatment and may not even be infected.”

Erik R. Dubberke



In an accompanying editorial, Erik R. Dubberke, MD, MSPH, and Carey-Anne D. Burnham, PhD, from Washington University School of Medicine in St. Louis, wrote that this study “contributes to the mounting evidence that most additional positive results of PCR-based C. difficile diagnostics compared with toxin [enzyme immunoassays] represent asymptomatic colonization, not [C. difficile infection]. Regardless of which assay is used, it is best to remember to treat the patient, not the test.” – by Adam Leitenberger

Disclosure: Polage reports he received research materials from Meridian Biosciences, Cepheid, TechLab and Alere, and honoraria for a webinar about diagnostic testing for C. difficile and nosocomial diarrhea from Alere. Please see the study for a full list of all other researchers’ relevant financial disclosures. Dubberke and Burnham report no relevant financial disclosures.