0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era

Christopher R. Polage, MD, MAS1,2; Clare E. Gyorke, BS1; Michael A. Kennedy, BS1; Jhansi L. Leslie, BS1,3; David L. Chin, PhD4; Susan Wang, BS1,5; Hien H. Nguyen, MD, MAS2; Bin Huang, MD, PhD6,7; Yi-Wei Tang, MD, PhD6,8; Lenora W. Lee, MD2; Kyoungmi Kim, PhD9; Sandra Taylor, PhD9; Patrick S. Romano, MD, MPH4,10,11; Edward A. Panacek, MD, MPH12; Parker B. Goodell, BS, MPH12; Jay V. Solnick, MD, PhD2,13; Stuart H. Cohen, MD2
[+] Author Affiliations
1Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento
2Division of Infectious Diseases, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento
3Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor
4Center for Healthcare Policy and Research, University of California Davis, Sacramento
5Yolo County Health Department, Woodland, California
6Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
7Department of Clinical Laboratory, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
8Weill Medical College of Cornell University, New York, New York
9Division of Biostatistics, Department of Public Health Sciences, University of California Davis School of Medicine, Sacramento
10Division of General Medicine, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento
11Division of General Pediatrics, Department of Pediatrics, University of California Davis School of Medicine, Sacramento
12Department of Emergency Medicine, University of California Davis School of Medicine, Sacramento
13Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Sacramento
JAMA Intern Med. 2015;175(11):1792-1801. doi:10.1001/jamainternmed.2015.4114.
Text Size: A A A
Published online

Importance  Clostridium difficile is a major cause of health care–associated infection, but disagreement between diagnostic tests is an ongoing barrier to clinical decision making and public health reporting. Molecular tests are increasingly used to diagnose C difficile infection (CDI), but many molecular test-positive patients lack toxins that historically defined disease, making it unclear if they need treatment.

Objective  To determine the natural history and need for treatment of patients who are toxin immunoassay negative and polymerase chain reaction (PCR) positive (Tox−/PCR+) for CDI.

Design, Setting, and Participants  Prospective observational cohort study at a single academic medical center among 1416 hospitalized adults tested for C difficile toxins 72 hours or longer after admission between December 1, 2010, and October 20, 2012. The analysis was conducted in stages with revisions from April 27, 2013, to January 13, 2015.

Main Outcomes and Measures  Patients undergoing C difficile testing were grouped by US Food and Drug Administration–approved toxin and PCR tests as Tox+/PCR+, Tox−/PCR+, or Tox−/PCR−. Toxin results were reported clinically. Polymerase chain reaction results were not reported. The main study outcomes were duration of diarrhea during up to 14 days of treatment, rate of CDI-related complications (ie, colectomy, megacolon, or intensive care unit care) and CDI-related death within 30 days.

Results  Twenty-one percent (293 of 1416) of hospitalized adults tested for C difficile were positive by PCR, but 44.7% (131 of 293) had toxins detected by the clinical toxin test. At baseline, Tox−/PCR+ patients had lower C difficile bacterial load and less antibiotic exposure, fecal inflammation, and diarrhea than Tox+/PCR+ patients (P < .001 for all). The median duration of diarrhea was shorter in Tox−/PCR+ patients (2 days; interquartile range, 1-4 days) than in Tox+/PCR+ patients (3 days; interquartile range, 1-6 days) (P = .003) and was similar to that in Tox−/PCR− patients (2 days; interquartile range, 1-3 days), despite minimal empirical treatment of Tox−/PCR+ patients. No CDI-related complications occurred in Tox−/PCR+ patients vs 10 complications in Tox+/PCR+ patients (0% vs 7.6%, P < .001). One Tox−/PCR+ patient had recurrent CDI as a contributing factor to death within 30 days vs 11 CDI-related deaths in Tox+/PCR+ patients (0.6% vs 8.4%, P = .001).

Conclusions and Relevance  Among hospitalized adults with suspected CDI, virtually all CDI-related complications and deaths occurred in patients with positive toxin immunoassay test results. Patients with a positive molecular test result and a negative toxin immunoassay test result had outcomes that were comparable to patients without C difficile by either method. 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.

Figures in this Article

Figures

Place holder to copy figure label and caption
Figure 1.
Flow of Patients Through Testing and Follow-up

Tox+/PCR+ indicates Clostridium difficile toxin immunoassay positive and polymerase chain reaction positive; Tox−/PCR+, C difficile toxin immunoassay negative and polymerase chain reaction positive; and Tox−/PCR−, C difficile toxin immunoassay negative and polymerase chain reaction negative.

aClostridium difficile test group based on US Food and Drug Administration–approved toxin immunoassay and polymerase chain reaction results.

bIncludes one patient with false-positive immunoassay.

cIncludes 20 patients with false-positive immunoassay.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Kaplan-Meier Curves of Time to Resolution of Diarrhea by Clostridium difficile Test Group

The median duration of diarrhea for patients with at least 1 day was 3 days (interquartile range, 1-6 days) for Tox+/PCR+ (121 of 131), 2 days (interquartile range, 1-4 days) for Tox−/PCR+, and 2 days (interquartile range, 1-3 days) for Tox−/PCR− (927 of 1123) (P < .001). Log-rank P values are P < .001 for all groups, P = .003 for Tox+/PCR+ vs Tox−/PCR+, (143 of 162) P < .001 for Tox+/PCR+ vs Tox−/PCR−, and P < .001 for Tox−/PCR+ vs Tox−/PCR−. Tox+/PCR+ indicates C difficile toxin immunoassay positive and polymerase chain reaction positive; Tox−/PCR+, C difficile toxin immunoassay negative and polymerase chain reaction positive; Tox−/PCR−, C difficile toxin immunoassay negative and polymerase chain reaction negative.

Graphic Jump Location

Tables

References

Correspondence

CME


You need to register in order to view this quiz.
Submit a Comment
The value of culture for toxigenic Clostridium difficile
Posted on November 6, 2015
Jill E. Clarridge
University of Washington and VA Med Center, Seattle
Conflict of Interest: None Declared
The results for culture for toxigenic Clostridium difficile were not clear. In the flow chart there were 9 specimens which were excluded from further analysis as nontoxigenic C. difficile were isolated. What were the culture results for the 3 other groups included in your analysis? It may be that culture and the EIA for toxin are both tests that are less sensitive than the PCR test and thus similarly might correlate with disease.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

10,690 Views
17 Citations
×

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles
Jobs
brightcove.createExperiences();