Diagnosis of Clostridium difficile Infection: an Ongoing Conundrum for Clinicians and for Clinical Laboratories

Abstract

SUMMARY Clostridium difficile is a formidable nosocomial and community-acquired pathogen, causing clinical presentations ranging from asymptomatic colonization to self-limiting diarrhea to toxic megacolon and fulminant colitis. Since the early 2000s, the incidence of C. difficile disease has increased dramatically, and this is thought to be due to the emergence of new strain types. For many years, the mainstay of C. difficile disease diagnosis was enzyme immunoassays for detection of the C. difficile toxin(s), although it is now generally accepted that these assays lack sensitivity. A number of molecular assays are commercially available for the detection of C. difficile . This review covers the history and biology of C. difficile and provides an in-depth discussion of the laboratory methods used for the diagnosis of C. difficile infection (CDI). In addition, strain typing methods for C. difficile and the evolving epidemiology of colonization and infection with this organism are discussed. Finally, considerations for diagnosing C. difficile disease in special patient populations, such as children, oncology patients, transplant patients, and patients with inflammatory bowel disease, are described. As detection of C. difficile in clinical specimens does not always equate with disease, the diagnosis of C. difficile infection continues to be a challenge for both laboratories and clinicians.

Strategies for Optimizing the Diagnostic Predictive Value of Clostridium difficile Molecular Diagnostics

“…Furthermore, because toxigenic culture does not identify the toxin in vivo, it does not reliably differentiate between CDI and asymptomatic C. difficile carriage. Toxigenic culture is considered to have greater sensitivity than CCCNA and is thus generally considered to be the preferred test between these two gold standards (2). Although stools that test toxigenic culture positive and CCCNA negative could potentially represent a false-negative CCCNA result, similar results could also occur in patients with asymptomatic C. difficile carriage.…”

“…Toxin EIAs have fallen out of favor in the United States because of perceived suboptimal sensitivity (i.e., frequent false-negative results) (6). However, closer examination of previous studies assessing performance of toxin EIAs demonstrates that toxin EIA sensitivity is generally higher in testing against CCCNA, the gold standard for toxin production, than against toxigenic culture, which does not detect free toxin in stool (2). Similarly to the concerns regarding CCCNA sensitivity described above, stools that test toxigenic culture positive and toxin EIA negative could represent asymptomatic C. difficile carriage rather than a falsely negative EIA result.…”

“…Because C. difficile toxin expression is the primary driver of C. difficile infection (CDI) symptomatology, the most specific C. difficile diagnostic tests detect free toxin in stool (2). The gold standard for toxin detection is the cell culture cytotoxicity neutralization assay (CCCNA).…”

“…Toxin EIAs represent the most commonly utilized commercially available assay for the detection of free toxin in stool (2). Toxin EIAs have fallen out of favor in the United States because of perceived suboptimal sensitivity (i.e., frequent false-negative results) (6).…”

“…Toxigenic culture is considered the gold standard for detecting a toxigenic strain of C. difficile in a stool specimen (2). First, C. difficile is cultured anaerobically.…”