Molecular Tests Linked to C difficile Overdiagnosis

Janis C. Kelly

September 11, 2015

Patients who test positive on polymerase chain reaction (PCR) tests for Clostridium difficile DNA may not be infected, and therefore not need treatment for C difficile infection (CDI), according to the results of a prospective observational study published online September 8 in JAMA Internal Medicine.

"Exclusive reliance on molecular tests for CDI diagnosis without tests for toxins or host response is likely to result in overdiagnosis, overtreatment, and increased health care costs," study author Christopher R. Polage, MD, from the Department of Pathology and Laboratory Medicine, University of California, Davis, School of Medicine, Sacramento, and colleagues write.

Polymerase chain reaction tests have been adopted by 44% of acute care hospitals since 2009, sometimes replacing the immunoassay test for C difficile toxins. This change has been accompanied by a 50% to 100% surge in reported rates of CDI, the authors note.

The researchers conducted a prospective observational cohort study of 1416 hospitalized adults with diarrhea to determine the natural history of patients who were positive by PCR testing but negative by toxin immunoassay (PCR+/TOX− 11.4%) to see how such they fared in comparison with patients positive on both tests (PCR+/TOX+ 9.3%) and those negative on both tests (PCR−/TOX− 79.3%), as well as to find out whether C difficile infection treatment is indicated for them. The primary outcome was duration of diarrhea during the first 15 days after sample collection, which could include up to 14 days of treatment. Standard treatment was 10 or more days of metronidazole or oral vancomycin.

The authors found that the 55.3% of patients who were PCR+/TOX− had outcomes no different from patients with similar symptoms who were negative on both tests, and the outcomes were not affected by whether the patients were treated for C difficile.

Table. Outcomes in Patients With Diarrhea Suspected of Having CDI

Characteristics (N = 1416) PCR+/TOX+ PCR+/TOX− PCR−/TOX−
9.3% (n = 131) 11.4% (n = 162) 79.3% (n = 1123)
Diarrhea duration (median) 3 days) 2 days) 2 days
CDI-related complications* 7.6% (n = 10) 0% (n = 0) 0.3% (3)
Recurrent CDI contributed to death within 30 days 8.4% (n = 11) 0.6% (n = 1) 0% (0)
Treated for CDI 100% (n = 131) 40.7% (n = 66) 32.1% (n = 361)

*Including megacolon, colectomy for fulminant colitis, and intensive care unit care related to CDI.

TOX− Patients Do Not Need Treatment for CDI

The PCR tests show whether C difficile is present, but not whether the organism is producing toxins and illness. "Our findings are consistent with the conventional view that CDI is a toxin-mediated inflammatory disease preceded by antibiotic exposure and C difficile overgrowth. Toxin-negative patients had less antibiotic exposure, C difficile DNA, and inflammation and manifested milder symptoms and no complications, despite minimal or no treatment," the authors write.

"These findings strongly suggest that most patients with negative toxin test results and C difficile detected by PCR do not need treatment for CDI. We suspect that most of these patients were colonized with C difficile and had another cause of diarrhea."

The authors point out that the number of patients potentially affected by these findings is "massive" and that there is urgent need for clinicians to understand that even symptomatic patients with positive PCR do not necessarily need treatment.

CDI Data Have Broad Implications

In an accompanying commentary, Erik R. Dubberke, MD, MSPH, and Carey-Ann D. Burnham, PhD, both from the Washington University School of Medicine, St. Louis, Missouri, note that 3% to 7% of healthy adults are colonized with C difficile, as are up to 15% of people admitted to hospitals and up to 50% of persons in long-term care facilities.

CDI is the cause in only 5% to 10% of hospitalized people who have diarrhea, according to Dr Dubberke and Dr Burnham. They point out that the low positive predictive values of the PCR test (44.7%) mean numerous false positives, and that for hospitals, this translates into the need for costly contact precautions such as single rooms and gowning.

They also note that careful selection of patients is needed before ordering CDI testing. "The few studies investigating this issue have found that 36% to 50% of hospitalized patients tested for C difficile do not have clinically significant diarrhea and that 20% to 44% of patients tested were on a laxative regimen. Improving patient selection for testing (eg, only testing patients with clinically significant diarrhea, as well as stopping laxative use before testing) will improve the positive predictive value of the assays," they write.

Finally, in view of the greater than 95% negative predictive value of toxin EIAs, Dr Dubberke and Dr Burnham advise that automatic repeat of a negative test result is not necessary, and that the risk for a false-positive increases with each round of toxin testing.

Dr Polage reported receiving C difficile diagnostic test kits and reagents from Meridian Biosciences, Cepheid, TechLab, and Alere and honoraria from Alere. One coauthor reported receiving research funding from Merck, Cubist, and Viropharma. Another coauthor reported receiving research funding and materials from ACEA Biosciences. Another coauthor reported serving on an advisory board for Merck and receiving research funding from Merck, Viropharma, Seres Health, and Actelion. The remaining coauthors have disclosed no relevant financial relationships.

JAMA Intern Med. Published online September 8, 2015. Article abstract, Commentary extract

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