Overdiagnosis of clostridium difficile infection in the molecular test era

Christopher R Polage, Clare E. Gyorke, Michael A. Kennedy, Jhansi L. Leslie, David L. Chin, Susan Wang, Hien H Nguyen, Bin Huang, Yi Wei Tang, Lenora W. Lee, Kyoungmi Kim, Sandra Taylor, Patrick S Romano, Edward A Panacek, Parker B. Goodell, Jay V Solnick, Stuart H Cohen

Research output: Contribution to journalArticle

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Abstract

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 testingwere 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.

Original languageEnglish (US)
Pages (from-to)1792-1801
Number of pages10
JournalJAMA Internal Medicine
Volume175
Issue number11
DOIs
StatePublished - Nov 1 2015

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Clostridium Infections
Clostridium difficile
Polymerase Chain Reaction
Infection
Immunoassay
Medical Overuse
Diarrhea
Outcome Assessment (Health Care)
Megacolon

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Overdiagnosis of clostridium difficile infection in the molecular test era. / Polage, Christopher R; Gyorke, Clare E.; Kennedy, Michael A.; Leslie, Jhansi L.; Chin, David L.; Wang, Susan; Nguyen, Hien H; Huang, Bin; Tang, Yi Wei; Lee, Lenora W.; Kim, Kyoungmi; Taylor, Sandra; Romano, Patrick S; Panacek, Edward A; Goodell, Parker B.; Solnick, Jay V; Cohen, Stuart H.

In: JAMA Internal Medicine, Vol. 175, No. 11, 01.11.2015, p. 1792-1801.

Research output: Contribution to journalArticle

Polage, CR, Gyorke, CE, Kennedy, MA, Leslie, JL, Chin, DL, Wang, S, Nguyen, HH, Huang, B, Tang, YW, Lee, LW, Kim, K, Taylor, S, Romano, PS, Panacek, EA, Goodell, PB, Solnick, JV & Cohen, SH 2015, 'Overdiagnosis of clostridium difficile infection in the molecular test era', JAMA Internal Medicine, vol. 175, no. 11, pp. 1792-1801. https://doi.org/10.1001/jamainternmed.2015.4114
Polage, Christopher R ; Gyorke, Clare E. ; Kennedy, Michael A. ; Leslie, Jhansi L. ; Chin, David L. ; Wang, Susan ; Nguyen, Hien H ; Huang, Bin ; Tang, Yi Wei ; Lee, Lenora W. ; Kim, Kyoungmi ; Taylor, Sandra ; Romano, Patrick S ; Panacek, Edward A ; Goodell, Parker B. ; Solnick, Jay V ; Cohen, Stuart H. / Overdiagnosis of clostridium difficile infection in the molecular test era. In: JAMA Internal Medicine. 2015 ; Vol. 175, No. 11. pp. 1792-1801.
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abstract = "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 testingwere 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.",
author = "Polage, {Christopher R} and Gyorke, {Clare E.} and Kennedy, {Michael A.} and Leslie, {Jhansi L.} and Chin, {David L.} and Susan Wang and Nguyen, {Hien H} and Bin Huang and Tang, {Yi Wei} and Lee, {Lenora W.} and Kyoungmi Kim and Sandra Taylor and Romano, {Patrick S} and Panacek, {Edward A} and Goodell, {Parker B.} and Solnick, {Jay V} and Cohen, {Stuart H}",
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TY - JOUR

T1 - Overdiagnosis of clostridium difficile infection in the molecular test era

AU - Polage, Christopher R

AU - Gyorke, Clare E.

AU - Kennedy, Michael A.

AU - Leslie, Jhansi L.

AU - Chin, David L.

AU - Wang, Susan

AU - Nguyen, Hien H

AU - Huang, Bin

AU - Tang, Yi Wei

AU - Lee, Lenora W.

AU - Kim, Kyoungmi

AU - Taylor, Sandra

AU - Romano, Patrick S

AU - Panacek, Edward A

AU - Goodell, Parker B.

AU - Solnick, Jay V

AU - Cohen, Stuart H

PY - 2015/11/1

Y1 - 2015/11/1

N2 - 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 testingwere 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.

AB - 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 testingwere 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.

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