Clostridium difficile is a Gram-positive, spore-forming, anaerobic bacillus that is associated with pseudomembranous colitis. The disease formerly known as C difficile-associated disease (CDAD) is now called C difficile infection (CDI). CDI ranges in severity from mild diarrhea to fulminant colitis. Risk factors for CDI include antibiotic use within three months prior to symptom onset and exposure to a health-care setting. Alterations of normal gut flora, resulting in overgrowth of C. difficile, are believed to initiate CDI. Production of exotoxins A & B by the organism subsequently results in colonic mucosal damage.
CDC data indicates that the incidence and severity of CDI has been increasing since the year 2000. Two publications (NEJM 2005; 353:2433-2449) described a more virulent strain of C. difficile that has been responsible for hospital outbreaks in the U.S. and Quebec, Canada. This epidemic strain differed from common strains in that it produces 16 times more toxin A and 23 times more toxin B. The epidemic strain was also resistant to fluoroquinolones. The epidemic strain produce more severe disease including toxic megacolon, leukemoid reaction, shock, and death, particularly in the elderly.
Equally alarming, community-acquired cases of severe CDAD in individuals with minimal risk factors were reported by the CDC (MMWR 2005;54:1201-1205). Analysis of the organism responsible for two of these infections showed they were not caused by the epidemic strain.
Common nonspecific laboratory abnormalities in patients with Clostridium difficile-associated disease (CDAD) include leukocytosis and hypoalbuminemia. Fecal leukocytes are detected in 50-60% of cases. Gram stains of fecal specimens are of no value, since C. difficile is only a small part of the fecal flora, even among patients with severe colitis. Likewise, anaerobic stool cultures are of little use in the diagnosis, due to the inability to distinguish between toxigenic and nontoxigenic strains.
Between 3% and 40% of children younger than 3 years and 3% to 26% of hospitalized children and adults are colonized with with toxigenic and nontoxigenic C difficile. Laboratory tests for C difficile need to distinguish between colonization and CDI.
Commonly used stool tests for detection of CDI include enzyme immunoassays (EIA) and PCR. EIA for glutamate dehydrogenase (GDH) antigen detects GDH protein which is present in both toxigenic and notoxigenic C difficile. PCR targets the tcdA & tcdB genes that encode for toxins A and B. GDH EIA and PCR have high sensitivity (94% and 96%, respectively) but lower specificity (94% and 90%, respectively) because they do not detect C difficile toxin. EIAs that detect C difficile toxins A and B have lower sensitivity for CDI (83%) but higher specificity (99%).
Multistep algorithms that include a test with high sensitivity (PCR or GDH EIA) and a test with high specificity (toxin EIA) improve the ability to distinguish CDI from C difficile colonization and avoid the prescription of unnecessary antibiotics. Negative PCR or GDH EIA results reliably exclude CDI because they have a negative predictive value of 98%. Patients with a positive toxin EIA are likely to have CDI. Patients with a positive PCR or GDH antigen result and a negative toxin EIA result may have symptomatic CDI or may be asymptomatic carriers of C difficile.
Guidelines from the Infectious Diseases Society of America (2017) state that PCR can be used alone for CDI testing in hospitals that have a diagnostic stewardship program. Clinicians and laboratorians need to be educated to perform PCR only for patients with unexplained new-onset diarrhea (defined as 3 or more unformed stools in 24 hours) who are not taking laxatives.
Specimens should be submitted fresh (refrigerated unless transported to the laboratory immediately) or in Cary-Blair transport media.
References
Nicholson MR and Donskey CJ. Multistep testing algorithms for Clostridioides difficile infection. JAMA Sep 12, 2023; 330:966-967.
McDonald CC et al. Clinical practice guidelines for clostridium difficile infection in adults and children: 2017 update by IDSA and SHEA. Nephrol Dial Transplant 2018;66(7)e1-e48.
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