A Laboratory Medicine Best Practices Systematic Review and Meta-analysis of Nucleic Acid Amplification Tests (NAATs) and Algorithms Including NAATs for the Diagnosis of Clostridioides (Clostridium) difficile in Adults

doi:10.1128/CMR.00032-18

Meta-Analysis

. 2019 May 29;32(3):e00032-18.

doi: 10.1128/CMR.00032-18. Print 2019 Jun 19.

A Laboratory Medicine Best Practices Systematic Review and Meta-analysis of Nucleic Acid Amplification Tests (NAATs) and Algorithms Including NAATs for the Diagnosis of Clostridioides (Clostridium) difficile in Adults

Colleen S Kraft¹, J Scott Parrott^{2

3}, Nancy E Cornish⁴, Matthew L Rubinstein⁴, Alice S Weissfeld⁵, Peggy McNult⁶, Irving Nachamkin⁷, Romney M Humphries⁸, Thomas J Kirn^{2

3}, Jennifer Dien Bard^{9

10}, Joseph D Lutgring¹¹, Jonathan C Gullett¹², Cassiana E Bittencourt¹³, Susan Benson^{14

15}, April M Bobenchik¹⁶, Robert L Sautter¹⁷, Vickie Baselski¹⁸, Michel C Atlas¹⁹, Elizabeth M Marlowe²⁰, Nancy S Miller^{21

22}, Monika Fischer²³, Sandra S Richter²⁴, Peter Gilligan²⁵, James W Snyder²⁶

Affiliations

¹ Emory University School of Medicine, Atlanta, Georgia, USA colleen.kraft@emory.edu jwsnyd01@louisville.edu.
² Department of Interdisciplinary Studies, School of Health Professions, Rutgers University, Newark, New Jersey, USA.
³ Department of Epidemiology, School of Public Health, Rutgers University, Piscataway, New Jersey, USA.
⁴ Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
⁵ Microbiology Specialists Incorporated, Houston, Texas, USA.
⁶ American Society for Microbiology, Washington, DC, USA.
⁷ Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Accelerate Diagnostics, Tucson, Arizona, USA.
⁹ Children's Hospital Los Angeles, Los Angeles, California, USA.
¹⁰ Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
¹¹ Emory University School of Medicine, Atlanta, Georgia, USA.
¹² Kaiser Permanente (Southern California Permanente Medical Group) Regional Reference Laboratories, Greater Los Angeles, Los Angeles, California, USA.
¹³ University of California-Irvine, Orange, California, USA.
¹⁴ PathWest Laboratory Medicine, Perth, Western Australia, Australia.
¹⁵ University of Western Australia, Perth, Western Australia, Australia.
¹⁶ Rhode Island Hospital/Lifespan Academic Medical Center, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
¹⁷ RL Sautter Consulting LLC, Lancaster, South Carolina, USA.
¹⁸ University of Tennessee Health Science Center, Memphis, Tennessee, USA.
¹⁹ Kornhauser Health Sciences Library, University of Louisville, Louisville, Kentucky, USA.
²⁰ Roche Molecular Systems, Pleasanton, California, USA.
²¹ Boston Medical Center, Boston, Massachusetts, USA.
²² Boston University School of Medicine, Boston, Massachusetts, USA.
²³ Indiana University, Indianapolis, Indiana, USA.
²⁴ Cleveland Clinic, Cleveland, Ohio, USA.
²⁵ University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
²⁶ Kornhauser Health Sciences Library, University of Louisville, Louisville, Kentucky, USA colleen.kraft@emory.edu jwsnyd01@louisville.edu.

PMID: 31142497
PMCID: PMC6589859
DOI: 10.1128/CMR.00032-18

Meta-Analysis

A Laboratory Medicine Best Practices Systematic Review and Meta-analysis of Nucleic Acid Amplification Tests (NAATs) and Algorithms Including NAATs for the Diagnosis of Clostridioides (Clostridium) difficile in Adults

Colleen S Kraft et al. Clin Microbiol Rev. 2019.

. 2019 May 29;32(3):e00032-18.

doi: 10.1128/CMR.00032-18. Print 2019 Jun 19.

Authors

Affiliations

¹ Emory University School of Medicine, Atlanta, Georgia, USA colleen.kraft@emory.edu jwsnyd01@louisville.edu.
² Department of Interdisciplinary Studies, School of Health Professions, Rutgers University, Newark, New Jersey, USA.
³ Department of Epidemiology, School of Public Health, Rutgers University, Piscataway, New Jersey, USA.
⁴ Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
⁵ Microbiology Specialists Incorporated, Houston, Texas, USA.
⁶ American Society for Microbiology, Washington, DC, USA.
⁷ Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Accelerate Diagnostics, Tucson, Arizona, USA.
⁹ Children's Hospital Los Angeles, Los Angeles, California, USA.
¹⁰ Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
¹¹ Emory University School of Medicine, Atlanta, Georgia, USA.
¹² Kaiser Permanente (Southern California Permanente Medical Group) Regional Reference Laboratories, Greater Los Angeles, Los Angeles, California, USA.
¹³ University of California-Irvine, Orange, California, USA.
¹⁴ PathWest Laboratory Medicine, Perth, Western Australia, Australia.
¹⁵ University of Western Australia, Perth, Western Australia, Australia.
¹⁶ Rhode Island Hospital/Lifespan Academic Medical Center, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
¹⁷ RL Sautter Consulting LLC, Lancaster, South Carolina, USA.
¹⁸ University of Tennessee Health Science Center, Memphis, Tennessee, USA.
¹⁹ Kornhauser Health Sciences Library, University of Louisville, Louisville, Kentucky, USA.
²⁰ Roche Molecular Systems, Pleasanton, California, USA.
²¹ Boston Medical Center, Boston, Massachusetts, USA.
²² Boston University School of Medicine, Boston, Massachusetts, USA.
²³ Indiana University, Indianapolis, Indiana, USA.
²⁴ Cleveland Clinic, Cleveland, Ohio, USA.
²⁵ University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
²⁶ Kornhauser Health Sciences Library, University of Louisville, Louisville, Kentucky, USA colleen.kraft@emory.edu jwsnyd01@louisville.edu.

PMID: 31142497
PMCID: PMC6589859
DOI: 10.1128/CMR.00032-18

Erratum in

Correction for Kraft et al., "A Laboratory Medicine Best Practices Systematic Review and Meta-analysis of Nucleic Acid Amplification Tests (NAATs) and Algorithms Including NAATs for the Diagnosis of Clostridioides (Clostridium) difficile in Adults".
Kraft CS, Parrott JS, Cornish NE, Rubinstein ML, Weissfeld AS, McNult P, Nachamkin I, Humphries RM, Kirn TJ, Dien Bard J, Lutgring JD, Gullett JC, Bittencourt CE, Benson S, Bobenchik AM, Sautter RL, Baselski V, Atlas MC, Marlowe EM, Miller NS, Fischer M, Richter SS, Gilligan P, Snyder JW. Kraft CS, et al. Clin Microbiol Rev. 2019 Aug 28;32(4):e00128-19. doi: 10.1128/CMR.00128-19. Print 2019 Sep 18. Clin Microbiol Rev. 2019. PMID: 31462404 Free PMC article. No abstract available.

Abstract

The evidence base for the optimal laboratory diagnosis of Clostridioides (Clostridium) difficile in adults is currently unresolved due to the uncertain performance characteristics and various combinations of tests. This systematic review evaluates the diagnostic accuracy of laboratory testing algorithms that include nucleic acid amplification tests (NAATs) to detect the presence of C. difficile The systematic review and meta-analysis included eligible studies (those that had PICO [population, intervention, comparison, outcome] elements) that assessed the diagnostic accuracy of NAAT alone or following glutamate dehydrogenase (GDH) enzyme immunoassays (EIAs) or GDH EIAs plus C. difficile toxin EIAs (toxin). The diagnostic yield of NAAT for repeat testing after an initial negative result was also assessed. Two hundred thirty-eight studies met inclusion criteria. Seventy-two of these studies had sufficient data for meta-analysis. The strength of evidence ranged from high to insufficient. The uses of NAAT only, GDH-positive EIA followed by NAAT, and GDH-positive/toxin-negative EIA followed by NAAT are all recommended as American Society for Microbiology (ASM) best practices for the detection of the C. difficile toxin gene or organism. Meta-analysis of published evidence supports the use of testing algorithms that use NAAT alone or in combination with GDH or GDH plus toxin EIA to detect the presence of C. difficile in adults. There is insufficient evidence to recommend against repeat testing of the sample using NAAT after an initial negative result due to a lack of evidence of harm (i.e., financial, length of stay, or delay of treatment) as specified by the Laboratory Medicine Best Practices (LMBP) systematic review method in making such an assessment. Findings from this systematic review provide clarity to diagnostic testing strategies and highlight gaps, such as low numbers of GDH/toxin/PCR studies, in existing evidence on diagnostic performance, which can be used to guide future clinical research studies.

Keywords: C. difficile infection; diagnostic accuracy; laboratory diagnosis; meta-analysis; systematic review.

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Figures

**FIG 1**
Analytic framework to address the question, How effective are NAAT practices for diagnosing patients suspected of having Clostridium difficile infection? Health care outcomes were not able to be considered in this systematic review; only intermediate outcomes could be assessed. On-demand versus batched testing could not be assessed because they were not listed in the literature.

**FIG 2**
Example use of the likelihood ratio scatter matrix to aid in the decision of effect size. LUQ, left upper quadrant; RUQ, right upper quadrant; LLQ, left lower quadrant; RLQ, right lower quadrant; LRP, positive likelihood ratio; LRN, negative likelihood ratio.

**FIG 4**
Scatter matrix of positive and negative likelihood ratios for NAAT-only detection of C. difficile. The red solid dots, in the scatter matrices, indicate the position of the combined +LR and −LR estimates. The whiskers running through the red dot are the confidence intervals for either +LR (vertical whiskers) or −LR (horizontal whiskers).

**FIG 5**
Scatter matrix of positive and negative likelihood ratios for GDH/NAAT algorithm detection of C. difficile. The red solid dots, in the scatter matrices, indicate the position of the combined +LR and −LR estimates. The whiskers running through the red dots are the confidence intervals for either +LR (vertical whiskers) or −LR (horizontal whiskers).

**FIG 6**
Scatter matrix of positive and negative likelihood ratios for GDH/toxin/NAAT algorithm detection of C. difficile. The red solid dots, in the scatter matrices, indicate the positions of the combined +LR and −LR estimates. The whiskers running through the red dots are the confidence intervals for either +LR (vertical whiskers) or −LR (horizontal whiskers).

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References

1. Schroeder LF, Robilotti E, Peterson LR, Banaei N, Dowdy DW. 2014. Economic evaluation of laboratory testing strategies for hospital-associated Clostridium difficile infection. J Clin Microbiol 52:489–496. doi:10.1128/JCM.02777-13. - DOI - PMC - PubMed
1. Miller BA, Chen LF, Sexton DJ, Anderson DJ. 2011. Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals. Infect Control Hosp Epidemiol 32:387–390. doi:10.1086/659156. - DOI - PubMed
1. Lessa FC, Winston LG, McDonald LC, Emerging Infections Program C. difficile Surveillance Team. 2015. Burden of Clostridium difficile infection in the United States. N Engl J Med 372:2369–2370. doi:10.1056/NEJMc1505190. - DOI - PMC - PubMed
1. Magee G, Strauss ME, Thomas SM, Brown H, Baumer D, Broderick KC. 2015. Impact of Clostridium difficile-associated diarrhea on acute care length of stay, hospital costs, and readmission: a multicenter retrospective study of inpatients, 2009-2011. Am J Infect Control 43:1148–1153. doi:10.1016/j.ajic.2015.06.004. - DOI - PubMed
1. Gao T, He B, Pan Y, Deng Q, Sun H, Liu X, Chen J, Wang S, Xia Y. 2015. Association of Clostridium difficile infection in hospital mortality: a systematic review and meta-analysis. Am J Infect Control 43:1316–1320. doi:10.1016/j.ajic.2015.04.209. - DOI - PubMed

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[1] Schroeder LF, Robilotti E, Peterson LR, Banaei N, Dowdy DW. 2014. Economic evaluation of laboratory testing strategies for hospital-associated Clostridium difficile infection. J Clin Microbiol 52:489–496. doi:10.1128/JCM.02777-13. - DOI - PMC - PubMed

[2] Schroeder LF, Robilotti E, Peterson LR, Banaei N, Dowdy DW. 2014. Economic evaluation of laboratory testing strategies for hospital-associated Clostridium difficile infection. J Clin Microbiol 52:489–496. doi:10.1128/JCM.02777-13. - DOI - PMC - PubMed

[3] Miller BA, Chen LF, Sexton DJ, Anderson DJ. 2011. Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals. Infect Control Hosp Epidemiol 32:387–390. doi:10.1086/659156. - DOI - PubMed

[4] Miller BA, Chen LF, Sexton DJ, Anderson DJ. 2011. Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals. Infect Control Hosp Epidemiol 32:387–390. doi:10.1086/659156. - DOI - PubMed

[5] Lessa FC, Winston LG, McDonald LC, Emerging Infections Program C. difficile Surveillance Team. 2015. Burden of Clostridium difficile infection in the United States. N Engl J Med 372:2369–2370. doi:10.1056/NEJMc1505190. - DOI - PMC - PubMed

[6] Lessa FC, Winston LG, McDonald LC, Emerging Infections Program C. difficile Surveillance Team. 2015. Burden of Clostridium difficile infection in the United States. N Engl J Med 372:2369–2370. doi:10.1056/NEJMc1505190. - DOI - PMC - PubMed

[7] Magee G, Strauss ME, Thomas SM, Brown H, Baumer D, Broderick KC. 2015. Impact of Clostridium difficile-associated diarrhea on acute care length of stay, hospital costs, and readmission: a multicenter retrospective study of inpatients, 2009-2011. Am J Infect Control 43:1148–1153. doi:10.1016/j.ajic.2015.06.004. - DOI - PubMed

[8] Magee G, Strauss ME, Thomas SM, Brown H, Baumer D, Broderick KC. 2015. Impact of Clostridium difficile-associated diarrhea on acute care length of stay, hospital costs, and readmission: a multicenter retrospective study of inpatients, 2009-2011. Am J Infect Control 43:1148–1153. doi:10.1016/j.ajic.2015.06.004. - DOI - PubMed

[9] Gao T, He B, Pan Y, Deng Q, Sun H, Liu X, Chen J, Wang S, Xia Y. 2015. Association of Clostridium difficile infection in hospital mortality: a systematic review and meta-analysis. Am J Infect Control 43:1316–1320. doi:10.1016/j.ajic.2015.04.209. - DOI - PubMed

[10] Gao T, He B, Pan Y, Deng Q, Sun H, Liu X, Chen J, Wang S, Xia Y. 2015. Association of Clostridium difficile infection in hospital mortality: a systematic review and meta-analysis. Am J Infect Control 43:1316–1320. doi:10.1016/j.ajic.2015.04.209. - DOI - PubMed

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A Laboratory Medicine Best Practices Systematic Review and Meta-analysis of Nucleic Acid Amplification Tests (NAATs) and Algorithms Including NAATs for the Diagnosis of Clostridioides (Clostridium) difficile in Adults

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A Laboratory Medicine Best Practices Systematic Review and Meta-analysis of Nucleic Acid Amplification Tests (NAATs) and Algorithms Including NAATs for the Diagnosis of Clostridioides (Clostridium) difficile in Adults

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