Point-Counterpoint: What Is the Optimal Approach for Detection of Clostridium difficile Infection?

Abstract

INTRODUCTION In 2010, we published an initial Point-Counterpoint on the laboratory diagnosis of Clostridium difficile infection (CDI). At that time, nucleic acid amplification tests (NAATs) were just becoming commercially available, and the idea of algorithmic approaches to CDI was being explored. Now, there are numerous NAATs in the marketplace, and based on recent proficiency test surveys, they have become the predominant method used for CDI diagnosis in the United States. At the same time, there is a body of literature that suggests that NAATs lack clinical specificity and thus inflate CDI rates. Hospital administrators are taking note of institutional CDI rates because they are publicly reported. They have become an important metric impacting hospital safety ratings and value-based purchasing; hospitals may have millions of dollars of reimbursement at risk. In this Point-Counterpoint using a frequently asked question approach, Ferric Fang of the University of Washington, who has been a consistent advocate for a NAAT-only approach for CDI diagnosis, will discuss the value of a NAAT-only approach, while Christopher Polage of the University of California Davis and Mark Wilcox of Leeds University, Leeds, United Kingdom, each of whom has recently written important articles on the value of toxin detection in the diagnosis, will discuss the impact of toxin detection in CDI diagnosis.

Clostridium difficile PCR Cycle Threshold Predicts Free Toxin

“…Given the lack of a stand-alone C. difficile diagnostic that can sensitively and rapidly detect free toxins in stool, some experts recommend a multistep testing algorithm in which a nucleic acid amplification test (NAAT) or EIA GDH is performed in tandem with EIA toxin to rapidly identify toxin-positive and toxin Ϫ /NAAT ϩ patients to facilitate appropriate clinical decision-making (3,4). Proponents of toxin testing recommend that only toxin-positive patients be treated for CDI and toxin Ϫ /NAAT ϩ patients be evaluated clinically to determine if they have CDI or are colonized with C. difficile (3,4).…”

“…Proponents of toxin testing recommend that only toxin-positive patients be treated for CDI and toxin Ϫ /NAAT ϩ patients be evaluated clinically to determine if they have CDI or are colonized with C. difficile (3,4). In this study, we showed that by defining a C T cutoff for GeneXpert C. difficile/Epi tcdB PCR, a sample-to-answer real-time PCR assay, we could sensitively predict 96.0% of toxin ϩ / PCR ϩ stool samples with an NPV of 97.1% and with a specificity of 78.0% using RMEIA toxin and CCNA as the reference method.…”

“…EIA glutamate dehydrogenase (GDH) is also used to detect C. difficile, but follow-up EIA toxin or PCR is needed to confirm toxigenicity. The best laboratory algorithm for diagnosing C. difficile infection (CDI) is debated (3). Compared to EIA toxin, PCR has a higher sensitivity for detection of toxigenic C. difficile in stool (4).…”

“…However, not all studies support this view (9)(10)(11)(12). Some experts recommend using highly sensitive PCR to avoid missing toxin Ϫ /PCR ϩ CDI cases because EIA toxin is less sensitive compared with cell cytotox-icity neutralization assay (CCNA), which is the gold standard for fecal free toxin but takes several days to perform (3). To address these diagnostic challenges, European guidelines recommend a multistep testing algorithm starting with PCR or EIA GDH and followed by EIA toxin to rapidly identify toxin-positive and toxin Ϫ /PCR ϩ patients to facilitate appropriate clinical decision-making (4).…”

Appropriate Use and Future Directions of Molecular Diagnostic Testing

“…These categories are complicated by the association of many medications, including antimicrobials, with diarrhea, as well as overlapping symptoms between CDI and viral causes of hospital-acquired diarrhea and increased likelihood of C. difficile colonization in individuals with antibiotic and healthcare exposures [28]. There is intense debate around the use of antigen testing versus molecular for the diagnosis of CDI, which is beyond the scope of this review [29]. Suffice to say that diagnostic and ASP partnerships are necessary to reduce syndromic GI panel testing that detects colonization and subsequent unnecessary treatment.…”