A Laboratory Medicine Best Practices Systematic Review and Meta-analysis of Nucleic Acid Amplification Tests (NAATs) and Algorithms Including NAATs for the Diagnosis of Clostridioides ( Clostridium ) difficile in Adults

Abstract

SUMMARY The evidence base for the optimal laboratory diagnosis of Clostridioides (Clostridium) difficile in adults is currently unresolved due to the uncertain performance characteristics and various combinations of tests. This systematic review evaluates the diagnostic accuracy of laboratory testing algorithms that include nucleic acid amplification tests (NAATs) to detect the presence of C. difficile. The systematic review and meta-analysis included eligible studies (those that had PICO [population, intervention, comparison, outcome] elements) that assessed the diagnostic accuracy of NAAT alone or following glutamate dehydrogenase (GDH) enzyme immunoassays (EIAs) or GDH EIAs plus C. difficile toxin EIAs (toxin). The diagnostic yield of NAAT for repeat testing after an initial negative result was also assessed. Two hundred thirty-eight studies met inclusion criteria. Seventy-two of these studies had sufficient data for meta-analysis. The strength of evidence ranged from high to insufficient. The uses of NAAT only, GDH-positive EIA followed by NAAT, and GDH-positive/toxin-negative EIA followed by NAAT are all recommended as American Society for Microbiology (ASM) best practices for the detection of the C. difficile toxin gene or organism. Meta-analysis of published evidence supports the use of testing algorithms that use NAAT alone or in combination with GDH or GDH plus toxin EIA to detect the presence of C. difficile in adults. There is insufficient evidence to recommend against repeat testing of the sample using NAAT after an initial negative result due to a lack of evidence of harm (i.e., financial, length of stay, or delay of treatment) as specified by the Laboratory Medicine Best Practices (LMBP) systematic review method in making such an assessment. Findings from this systematic review provide clarity to diagnostic testing strategies and highlight gaps, such as low numbers of GDH/toxin/PCR studies, in existing evidence on diagnostic performance, which can be used to guide future clinical research studies.

Multicenter Prevalence Study Comparing Molecular and Toxin Assays for Clostridioides difficile Surveillance, Switzerland

“…In addition, the clinical practice guidelines for CDI in adults and children published by the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America recommend testing by different approaches, such as multistep algorithms or NAAT, depending on the degree of clinical suspicion (17). Based on a systematic review and meta-analysis, the American Society of Microbiology also recommends different approaches, including NAAT-only testing, and algorithms that include GDH and NAAT or GDH, toxins, and NAAT (18). Although these recommendations stand to reason for detection of CDI in individual patients, our results challenge their utility for meaningful comparisons in surveillance studies and suggest that uniform definitions should be provided.…”

Diagnostic Algorithm for the Rapid and Cost- Effective Detection of Clostridioides difficile Infection: Comparison between C. DIFF QUIK CHEK COMPLETE and VIDAS GDH & Toxin Assay

“…In our institution, the actual average TAT per sample for the twostep algorithms was just 7.6-8.7 minutes more compared to each of the first step methods (QCC and VIDAS). The TAT of the two-step algorithm using the QCC assay (47.6 minutes) was similar to the one-step method using the Xpert assay (50 minutes) in our institution ( Table 3) the best practice for detecting the C. difficile toxin gene [16] as the widely-used Xpert assay demonstrated good sensitivity and specificity, comparable to CCNA or TC [10,24,32]. Therefore, the use of the Xpert assay as a reference method in this study should not have affected our findings.…”

“…However, they do not detect free toxins and therefore cannot differentiate between colonization and disease [24,25]. Rapid NAAT, as a single diagnostic method, could lead to decreases in the length of stay (approximately 2 days), days on empiric CDI treatment and isolation, and associated costs [17,26].…”

Clinical evaluation of a non-purified direct molecular assay for the detection of Clostridioides difficile toxin genes in stool specimens

“…In the previous studies, the sensitivity between molecular assays and toxigenic culture have been reported as 82%-97% for the BD MAX Cdiff assay [7,10,15,28] and 83%-100% for the Xpert C. difficile [7,10,15,28,29]. Based on these results, we consider that the GENECUBE C. difficile assay has sufficient ability as a molecular assay.…”