CONTINUING EDUCATION :: C DIFFICILE
Figure 2. FDA-approved tests for C. difficile should be used with clinical history to diagnose CDI years.2
The most recent guideline is from the American College of Gastroenterologists (ACG).3
The ACG recommendations follow
those from ESCMID and IDSA/SHEA. The ACG guidelines note that the case numbers of CDI in- creased significantly when many hospitals and healthcare facili- ties implemented NAAT assays, and the authors raised concerns that asymptomatic patients who were colonized with C. difficile tested positive, and there are other causes of diarrhea in patients colonized with toxigenic strains. The ACG guideline note further that complications are rare in patients who are NAAT-positive but negative for toxin. For these reasons, the ACG guidelines recommend an algorithm comprised of NAAT or GDH testing coupled with toxin testing.3
These recommendations are directly
in-line with those from ESCMID and IDSA/SHEA. The IDSA/SHEA guidelines note that if specimen selection
criteria are in place, the accuracy of a NAAT assay improves and recommend that a NAAT assay may be used as a stand-alone test under these conditions. Whether appropriate specimen selection procedures can be implemented in most hospital settings was a point of discussion at the recent 9th Annual International C. DIFF Conference and Health EXPO, which was held in November 2021. Algorithm testing is considered optimal because it brings to- gether the high NPV of GDH or NAAT assays with the high PPV of a toxin test, helping to limit false negative and false positive results, respectively. When used as the initial screen, GDH or NAAT assays accurately rule out patients who do not have CDI. This will be the majority of patients in most hospitals. Follow-up toxin testing with specimens that are GDH-positive or NAAT- positive provides the most accurate information to the physician tasked with diagnosing CDI. This approach provides confirma- tory results for >90% of specimens submitted for testing. Of the remaining low number of specimens that are positive by GDH or NAAT but negative for toxin, the ESCMID guidelines define these patients as carriers, although some probably have true CDI.
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Efforts have been made by several companies to produce ul- trasensitive toxin tests.4
These types of tests have the potential to
simplify laboratory testing and the reporting structure for CDI, assuming they can provide adequate sensitivity. However, these tests also need to exhibit high specificity to achieve the PPVs now available with higher quality FDA-cleared toxin immunoassays. Many patients will continue to test positive for weeks or months by NAAT even after symptoms have resolved because of the persistence of spores. Resolution of symptoms more ac- curately correlates with the disappearance of toxin. Even so, none of the guidelines recommends a “test of cure” for CDI. Repeat testing is not routinely recommended, although on oc- casion, it may be performed to confirm recurrent CDI. All of the guidelines stress that the diagnosis and decision to treat is a clinical decision, and that laboratory tests “aid” but do not diagnose CDI.
CDI is an inflammatory disease Inflammation is a hallmark of CDI. The inflammatory process is triggered by the toxins and the tissue damage they cause to the gut mucosa. Both toxins are glucosyltransferases that bind to cellular receptors and kill cells by shutting down the cytoskeletal system. In addition, both toxins trigger inflamma- tory mediators that result in the diapedesis of white blood cells (WBCs) into the intestinal lumen. White blood cells become activated and stimulate the release of proinflammatory media- tors. The multimeric inflammasomes that develop result in additional inflammation. The severity of the disease can be monitored by circulating WBC counts, with >15,000 per mm3
signaling severe disease.
Fecal lactoferrin, a stable glycoprotein released from WBCs that migrate into the intestinal lumen, can be measured quantita- tively in fecal specimens as a direct measurement of intestinal inflammation. Fecal lactoferrin and circulating WBC counts
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