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Overdiagnosis of Clostridium difficile

Between 4.4% and 15% of people are colonized with Clostridium difficile on admission to the hospital. The incidence of colonization may be as high as 50% in persons living in long-term care facilities. The incidence of colonization is much higher than the incidence of Clostridium difficile infection (CDI). CDI affects less than 1% of hospitalized patients and is the cause of diarrhea in only 5% to 10% of hospitalized people who have diarrhea and are tested for Clostridium difficile. Unfortunately, none of the current polymerase chain reaction (PCR) or toxin enzyme immunoassay (EIA) tests can distinguish CDI from colonization in the absence of clinical data.

A recent study by Polage et aldemonstrated that patients who tested negative for Clostridium difficile toxin and positive by PCR (Tox?/PCR+) experienced significantly less severe diarrhea, more rapid recovery, and fewer complications or deaths than patients who tested positive for both toxin and PCR (Tox+/PCR+). The presentation and outcomes of patients that were Tox?/PCR+ were no different than patients who tested negative for both toxin toxin and PCR (Tox-/PCR-).

Patients who test positive for toxin have higher bacterial and toxin levels and higher levels of inflammatory markers than patients who test positive by PCR alone, indicating that those positive by PCR alone are more likely to have asymptomatic Clostridium difficile colonization than CDI.

More patients were Tox-/PCR+ than were Tox+/PCR+. When clinical presentation is considered, PCR had a sensitivity of 100%, specificity of 87.4%, and a positive predictive value of 44.7%. The negative predictive value of toxin EIA is at least 95%. PCR testing alone has numerous false positive results.

CDC has estimated that the incidence of CDI increased by 43 to 67% at hospitals that changed from Clostridium difficile toxin EIA to PCR assays for detection. This increased positive rate has serious implications for hospitals and patients. More positive assays result in more patients placed under contact precautions. Patients with false positive results receive CDI treatment, which increases their risk of drug-related adverse events, selection for multidrug- resistant organisms, and a higher risk for CDI after treatment is stopped.

Because there is no perfect test to distinguish colonization from infection, physicians need to be aware of the limitations of current laboratory tests and improve patient selection for testing. Only those patients with clinically significant diarrhea should be tested. Laxative use should be stopped prior to testing.

Polage CR,Gyorke CE,Kennedy MA,etal. Overdiagnosis of Clostridium difficile infection in the molecular test era [published online September 8, 2015]. JAMA Intern Med. doi:10.1001 /jamainternmed.2015.4114.

Dubberke ER and Burnham CAD, Diagnosis of Clostridium difficile infection: Treat the patient, not the test. JAMA Internal Med. 2015; 175:1801-1802.

Planche TD,Davies KA,Coen PG,etal. Differences in outcome according to Clostridium difficile testing method: a prospective multicentre diagnostic validation study of C difficile infection. Lancet Infect Dis. 2013;13(11):936-945.

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