Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era.
OBJECTIVE
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.


METHODS
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.


METHODS
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
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.
Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento2Division of Infectious Diseases, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento.
Christopher R
CR
Polage
Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento.
Clare E
CE
Gyorke
Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento.
Michael A
MA
Kennedy
Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento3Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor.
Jhansi L
JL
Leslie
Center for Healthcare Policy and Research, University of California Davis, Sacramento.
David L
DL
Chin
Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento5Yolo County Health Department, Woodland, California.
Susan
S
Wang
Division of Infectious Diseases, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento.
Hien H
HH
Nguyen
Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York7Department of Clinical Laboratory, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Bin
B
Huang
Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York8Weill Medical College of Cornell University, New York, New York.
Yi-Wei
YW
Tang
Division of Infectious Diseases, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento.
Lenora W
LW
Lee
Division of Biostatistics, Department of Public Health Sciences, University of California Davis School of Medicine, Sacramento.
Kyoungmi
K
Kim
Division of Biostatistics, Department of Public Health Sciences, University of California Davis School of Medicine, Sacramento.
Sandra
S
Taylor
Center for Healthcare Policy and Research, University of California Davis, Sacramento10Division of General Medicine, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento11Division of General Pediatrics, Department.
Patrick S
PS
Romano
Department of Emergency Medicine, University of California Davis School of Medicine, Sacramento.
Edward A
EA
Panacek
Department of Emergency Medicine, University of California Davis School of Medicine, Sacramento.
Parker B
PB
Goodell
Division of Infectious Diseases, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento13Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Sacramento.
Jay V
JV
Solnick
Division of Infectious Diseases, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento.
Stuart H
SH
Cohen
D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001427:Bacterial Toxins / Q000032:analysis*; D016360:Clostridioides difficile / Q000302:isolation & purification*; D003015:Clostridium Infections / Q000175:diagnosis / Q000188:drug therapy / Q000382:microbiology; D015331:Cohort Studies; D003428:Cross Infection / Q000175:diagnosis / Q000188:drug therapy / Q000382:microbiology; D005260:Female; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D000069342:Medical Overuse / Q000517:prevention & control / Q000706:statistics & numerical data; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000706:statistics & numerical data*; D011446:Prospective Studies; D014481:United States
D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins