Molecular Tests Should Not be Standalone Diagnostic for C. Diff

Exclusive reliance on molecular tests for Clostridium difficile (C. diff) infection diagnosis is likely to result in overdiagnosis, overtreatment, and increased health care costs, according to a study published in the November issue of JAMA Internal Medicine. Virtually all C. diff infection-related complications and deaths occur in patients with positive toxin immunoassay test results, not just positive molecular test results, indicating that treatment is likely unnecessary based solely on molecular testing.

"Molecular tests should not be used as a stand-alone diagnostic test for CDI and diagnostic recommendations should move back in the direction of defining clinical disease as a positive toxin result in patients with diarrhea," write the authors led by Christopher Polage, M.D., from University of California, Davis. "Two-step testing with a screening test, such as polymerase chain reaction or glutamate dehydrogenase antigen detection, followed by a toxin test to confirm active infection is a reasonable diagnostic strategy."

Molecular tests are increasingly used to diagnose C diff infection, but many molecular test-positive patients lack toxins that historically defined diagnosis, leading to some confusion as to which patients need treatment for pathogenic C. diff infections and which ones may just have bacterial colonization. The number of institutions using molecular tests is growing rapidly, with 44 percent of hospitals adopting the molecular test (alone or in combination) in 2014. Previous research has shown that adoption of molecular C. diff testing has increased the rates of C. diff reporting by as much as 100 percent.

In the JAMA study, an academic medical center tested 1,416 hospitalized adults (Dec. 2010 through Oct. 20, 2012) with suspected CDI with U.S. Food and Drug Administration-approved polymerase chain reaction (PCR) molecular tests (Xpert C. difficile/Ep [Cepheid]; and illumigene C. difficile [Meridian Biosciences]), while maintaining existing toxin testing for clinical diagnosis (C difficile Premier toxins A and B; Meridian Biosciences). Clinical outcome and treatment data were also evaluated. Patients were grouped by both toxin and PCR tests results: Tox+/PCR+, Tox−/PCR+, or Tox−/PCR−.

The researchers found that more than half (55.3 percent) of 293 PCR+ patients lacked the toxin on the clinical toxin immunoassay test. These Tox-/PCR+ patients had clinical outcomes that were comparable to patients with no C difficile detected. At baseline, Tox−/PCR+ patients had significantly lower C diff bacterial load, as well as less antibiotic exposure and diarrhea than Tox+/PCR+ patients. The vast majority of C. diff infection-related complications, including deaths, occurred in Tox+/PCR+ patients. In total, 58.7 percent of the 162 Tox-/PCR+ patients were never retested, and only 13.0 percent received a full course of treatment.

"Our results offer compelling evidence that as many as half of the patients with positive C difficile PCR test results are likely to be overdiagnosed and exposed to unnecessary treatment at institutions using molecular tests," write the authors. "The number of patients potentially affected by this issue is massive."

The authors urge laboratories to realize that rejection of formed stool samples is "not sufficient" to ensure that all positive molecular C. diff results represent disease. The authors also cite the need to educate physicians to recognize that molecular tests are not specific for C. diff infection and that even in the presence of symptoms patients with positive PCR results do not necessarily need treatment. Lastly, the authors say new diagnostic development should focus on quantification of C. diff DNA, toxins, or host response to distinguish patients with active C. diff infections from those with colonization.

Takeaway: Despite growing adoption of molecular-based C. diff tests, these tests should not be employed alone as they likely result in overdiagnosis of C. diff infection in a sizable portion of those tested, who will recover without treatment.