Abstract
Diagnosis of Clostridium difficile infection (CDI) can be challenging. First of all, there has been debate on which of the two reference assays, cell cytotoxicity neutralization assay (CCNA) or toxigenic culture (TC) should be considered the gold standard for CDI detection. Although the CCNA suffers most from suboptimal storage conditions and subsequent toxin degradation, TC is reported to falsely increase CDI detection rates as it cannot differentiate CDI patients from patients asymptomatically colonised by toxigenic C. difficile. Several rapid assays are available for CDI detection and fall into three broad categories: (1) enzyme immunoassays for glutamate dehydrogenase, (2) enzyme immunoassays for toxins A/B and (3) nucleic acid amplification tests detecting toxin genes. All three categories have their own limitations, being suboptimal specificity and/or sensitivity or the inability to discern colonised patients from CDI patients. In light of these limitations, multi-step algorithmic testing has now been advocated by international guidelines in order to optimize diagnostic accuracy. Despite these recommendations, testing methods between hospitals vary widely, which impacts CDI incidence rates. CDI incidence rates are also influenced by sample selection criteria, as several studies have shown that if not all unformed stool samples are tested for CDI, many cases may be missed due to an absence of clinical suspicion. Since methods for diagnosing CDI remain imperfect, there has been a growing interest in alternative testing strategies like faecal biomarkers, immune modulating interleukins, cytokines and imaging methods. At the moment, these alternative methods might play an adjunctive role, but they are not suitable to replace conventional CDI testing strategies.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Aichinger E, Schleck CD, Harmsen WS, Nyre LM, Patel R (2008) Nonutility of repeat laboratory testing for detection of Clostridium difficile by use of PCR or enzyme immunoassay. J Clin Microbiol 46(11):3795–3797. https://doi.org/10.1128/jcm.00684-08
Alcala L, Martin A, Marin M, Sanchez-Somolinos M, Catalan P, Pelaez T, Bouza E (2012) The undiagnosed cases of Clostridium difficile infection in a whole nation: where is the problem? Clin Microbiol Infect 18(7):E204–E213. https://doi.org/10.1111/j.1469-0691.2012.03883.x
Archbald-Pannone LR (2014) Quantitative fecal lactoferrin as a biomarker for severe Clostridium difficile infection in hospitalized patients. J Geriatr Palliat Care 2(1):3. https://doi.org/10.13188/2373-1133.1000006
Barbut F, Surgers L, Eckert C, Visseaux B, Cuingnet M, Mesquita C, Pradier N, Thiriez A, Ait-Ammar N, Aifaoui A, Grandsire E, Lalande V (2014) Does a rapid diagnosis of Clostridium difficile infection impact on quality of patient management? Clin Microbiol Infect 20(2):136–144. https://doi.org/10.1111/1469-0691.12221
Bartlett JG (2002) Clinical practice. Antibiotic-associated diarrhea. N Engl J Med 346(5):334–339. https://doi.org/10.1056/NEJMcp011603
Bartlett JG, Gerding DN (2008) Clinical recognition and diagnosis of Clostridium difficile infection. Clin Infect Dis 46(Suppl 1):S12–S18. https://doi.org/10.1086/521863
Berrington A, Settle CD (2007) Which specimens should be tested for Clostridium difficile toxin? J Hosp Infect 65(3):280–282. https://doi.org/10.1016/j.jhin.2006.12.011
Bidet P, Barbut F, Lalande V, Burghoffer B, Petit JC (1999) Development of a new PCR-ribotyping method for Clostridium difficile based on ribosomal RNA gene sequencing. FEMS Microbiol Lett 175(2):261–266
Bogaty C, Levesque S, Garenc C, Frenette C, Bolduc D, Galarneau LA, Lalancette C, Loo V, Tremblay C, Trudeau M, Vachon J, Dionne M, Villeneuve J, Longtin J, Longtin Y (2017) Trends in the use of laboratory tests for the diagnosis of Clostridium difficile infection and association with incidence rates in Quebec, Canada, 2010–2014. Am J Infect Control 45(9):964–968. https://doi.org/10.1016/j.ajic.2017.04.002
Boone JH, DiPersio JR, Tan MJ, Salstrom SJ, Wickham KN, Carman RJ, Totty HR, Albert RE, Lyerly DM (2013) Elevated lactoferrin is associated with moderate to severe Clostridium difficile disease, stool toxin, and 027 infection. Eur J Clin Microbiol Infect Dis 32(12):1517–1523. https://doi.org/10.1007/s10096-013-1905-x
Boone JH, Archbald-Pannone LR, Wickham KN, Carman RJ, Guerrant RL, Franck CT, Lyerly DM (2014) Ribotype 027 Clostridium difficile infections with measurable stool toxin have increased lactoferrin and are associated with a higher mortality. Eur J Clin Microbiol Infect Dis 33(6):1045–1051. https://doi.org/10.1007/s10096-013-2043-1
Burnham CA, Carroll KC (2013) Diagnosis of Clostridium difficile infection: an ongoing conundrum for clinicians and for clinical laboratories. Clin Microbiol Rev 26(3):604–630. https://doi.org/10.1128/cmr.00016-13
CDC (2012) MMWR Morb Wkly Rep 61:157–162
Chung HS, Lee M (2017) Evaluation of the performance of C. DIFF QUIK CHEK COMPLETE and its usefulness in a hospital setting with a high prevalence of Clostridium difficile infection. J Investig Med 65(1):88–92. https://doi.org/10.1136/jim-2016-000231
Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepin J, Wilcox MH (2010) Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol 31(5):431–455. https://doi.org/10.1086/651706
Crobach MJ, Planche T, Eckert C, Barbut F, Terveer EM, Dekkers OM, Wilcox MH, Kuijper EJ (2016) European society of clinical microbiology and infectious diseases: update of the diagnostic guidance document for Clostridium difficile infection. Clin Microbiol Infect 22(Suppl 4):S63–S81. https://doi.org/10.1016/j.cmi.2016.03.010
Darkoh C, Turnwald BP, Koo HL, Garey KW, Jiang ZD, Aitken SL, DuPont HL (2014) Colonic immunopathogenesis of Clostridium difficile infections. Clin Vaccine Immunol 21(4):509–517. https://doi.org/10.1128/cvi.00770-13
Davies KA, Longshaw CM, Davis GL, Bouza E, Barbut F, Barna Z, Delmee M, Fitzpatrick F, Ivanova K, Kuijper E, Macovei IS, Mentula S, Mastrantonio P, von Muller L, Oleastro M, Petinaki E, Pituch H, Noren T, Novakova E, Nyc O, Rupnik M, Schmid D, Wilcox MH (2014) Underdiagnosis of Clostridium difficile across Europe: the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID). Lancet Infect Dis 14(12):1208–1219. https://doi.org/10.1016/S1473-3099(14)70991-0
Davies K, Davis G, Barbut F, Eckert C, Petrosillo N, Wilcox MH (2016a) Variability in testing policies and impact on reported Clostridium difficile infection rates: results from the pilot longitudinal European Clostridium difficile infection diagnosis surveillance study (LuCID). Eur J Clin Microbiol Infect Dis 35(12):1949–1956. https://doi.org/10.1007/s10096-016-2746-1
Debast SB, van Kregten E, Oskam KM, van den Berg T, Van den Berg RJ, Kuijper EJ (2008) Effect on diagnostic yield of repeated stool testing during outbreaks of Clostridium difficile-associated disease. Clin Microbiol Infect 14(6):622–624. https://doi.org/10.1111/j.1469-0691.2008.01999.x
Delmee M (2001) Laboratory diagnosis of Clostridium difficile disease. Clin Microbiol Infect 7(8):411–416
Dionne LL, Raymond F, Corbeil J, Longtin J, Gervais P, Longtin Y (2013) Correlation between Clostridium difficile bacterial load, commercial realtime PCR cycle thresholds, and results of diagnostic tests based on enzyme immunoassay and cell culture cytotoxicity assay. J Clin Microbiol 51(11):3624–3630. https://doi.org/10.1128/JCM.01444-13
El Feghaly RE, Stauber JL, Deych E, Gonzalez C, Tarr PI, Haslam DB (2013) Markers of intestinal inflammation, not bacterial burden, correlate with clinical outcomes in Clostridium difficile infection. Clin Infect Dis 56(12):1713–1721. https://doi.org/10.1093/cid/cit147
Enoch DA, Butler MJ, Pai S, Aliyu SH, Karas JA (2011) Clostridium difficile in children: colonisation and disease. J Inf Secur 63(2):105–113. https://doi.org/10.1016/j.jinf.2011.05.016
Fawley WN, Knetsch CW, MacCannell DR, Harmanus C, Du T, Mulvey MR, Paulick A, Anderson L, Kuijper EJ, Wilcox MH (2015) Development and validation of an internationally-standardized, high-resolution capillary gel-based electrophoresis PCR-ribotyping protocol for Clostridium difficile. PLoS One 10(2):e0118150. https://doi.org/10.1371/journal.pone.0118150
Green DA, Stotler B, Jackman D, Whittier S, Della-Latta P (2014) Clinical characteristics of patients who test positive for Clostridium difficile by repeat PCR. J Clin Microbiol 52(11):3853–3855. https://doi.org/10.1128/JCM.01659-14
Grein JD, Ochner M, Hoang H, Jin A, Morgan MA, Murthy AR (2014) Comparison of testing approaches for Clostridium difficile infection at a large community hospital. Clin Microbiol Infect 20(1):65–69. https://doi.org/10.1111/1469-0691.12198
Hensgens MP, Dekkers OM, Demeulemeester A, Buiting AG, Bloembergen P, van Benthem BH, Le Cessie S, Kuijper EJ (2014) Diarrhoea in general practice: when should a Clostridium difficile infection be considered? Results of a nested case-control study. Clin Microbiol Infect 20(12):O1067–O1074. https://doi.org/10.1111/1469-0691.12758
Hink T, Burnham CA, Dubberke ER (2013) A systematic evaluation of methods to optimize culture-based recovery of Clostridium difficile from stool specimens. Anaerobe 19:39–43. https://doi.org/10.1016/j.anaerobe.2012.12.001
Jazmati N, Hellmich M, Licanin B, Plum G, Kaasch AJ (2016) PCR cycle threshold value predicts the course of Clostridium difficile infection. Clin Microbiol Infect 22(2):e7–e8. https://doi.org/10.1016/j.cmi.2015.09.012
Kaltsas A, Simon M, Unruh LH, Son C, Wroblewski D, Musser KA, Sepkowitz K, Babady NE, Kamboj M (2012) Clinical and laboratory characteristics of Clostridium difficile infection in patients with discordant diagnostic test results. J Clin Microbiol 50(4):1303–1307. https://doi.org/10.1128/jcm.05711-11
Khanna S, Pardi DS, Rosenblatt JE, Patel R, Kammer PP, Baddour LM (2012) An evaluation of repeat stool testing for Clostridium difficile infection by polymerase chain reaction. J Clin Gastroenterol 46(10):846–849. https://doi.org/10.1097/MCG.0b013e3182432273
Killgore G, Thompson A, Johnson S, Brazier J, Kuijper E, Pepin J, Frost EH, Savelkoul P, Nicholson B, van den Berg RJ, Kato H, Sambol SP, Zukowski W, Woods C, Limbago B, Gerding DN, MD LC (2008) Comparison of seven techniques for typing international epidemic strains of Clostridium difficile: restriction endonuclease analysis, pulsed-field gel electrophoresis, PCR-ribotyping, multilocus sequence typing, multilocus variable-number tandem-repeat analysis, amplified fragment length polymorphism, and surface layer protein A gene sequence typing. J Clin Microbiol 46(2):431–437. https://doi.org/10.1128/jcm.01484-07
Kim J, Kim H, Oh HJ, Kim HS, Hwang YJ, Yong D, Jeong SH, Lee K (2017) Fecal calprotectin level reflects the severity of Clostridium difficile Infection. Ann Lab Med 37(1):53–57. https://doi.org/10.3343/alm.2017.37.1.53
Kirkpatrick ID, Greenberg HM (2001) Evaluating the CT diagnosis of Clostridium difficile colitis: should CT guide therapy? AJR Am J Roentgenol 176(3):635–639. https://doi.org/10.2214/ajr.176.3.1760635
Knetsch CW, Lawley TD, Hensgens MP, Corver J, Wilcox MW, Kuijper EJ (2013) Current application and future perspectives of molecular typing methods to study Clostridium difficile infections. Euro Surveill 18(4):20381
Kristjansson M, Samore MH, Gerding DN, DeGirolami PC, Bettin KM, Karchmer AW, Arbeit RD (1994) Comparison of restriction endonuclease analysis, ribotyping, and pulsed-field gel electrophoresis for molecular differentiation of Clostridium difficile strains. J Clin Microbiol 32(8):1963–1969
Kundrapu S, Sunkesula VC, Jury LA, Sethi AK, Donskey CJ (2012) Utility of perirectal swab specimens for diagnosis of Clostridium difficile infection. Clin Infect Dis 55(11):1527–1530. https://doi.org/10.1093/cid/cis707
Kyne L, Warny M, Qamar A, Kelly CP (2000) Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med 342(6):390–397. https://doi.org/10.1056/nejm200002103420604
LaSala PR, Ekhmimi T, Hill AK, Farooqi I, Perrotta PL (2013) Quantitative fecal lactoferrin in toxin-positive and toxin-negative Clostridium difficile specimens. J Clin Microbiol 51(1):311–313. https://doi.org/10.1128/jcm.02735-12
Leslie JL, Cohen SH, Solnick JV, Polage CR (2012) Role of fecal Clostridium difficile load in discrepancies between toxin tests and PCR: is quantitation the next step in C. difficile testing? Eur J Clin Microbiol Infect Dis 31(12):3295–3299. https://doi.org/10.1007/s10096-012-1695-6
Longtin Y, Trottier S, Brochu G, Paquet-Bolduc B, Garenc C, Loungnarath V, Beaulieu C, Goulet D, Longtin J (2013) Impact of the type of diagnostic assay on Clostridium difficile infection and complication rates in a mandatory reporting program. Clin Infect Dis 56(1):67–73. https://doi.org/10.1093/cid/cis840
Loo VG, Bourgault AM, Poirier L, Lamothe F, Michaud S, Turgeon N, Toye B, Beaudoin A, Frost EH, Gilca R, Brassard P, Dendukuri N, Beliveau C, Oughton M, Brukner I, Dascal A (2011) Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med 365(18):1693–1703. https://doi.org/10.1056/NEJMoa1012413
Luo RF, Banaei N (2010) Is repeat PCR needed for diagnosis of Clostridium difficile infection? J Clin Microbiol 48(10):3738–3741. https://doi.org/10.1128/jcm.00722-10
Maiden MC, Bygraves JA, Feil E, Morelli G, Russell JE, Urwin R, Zhang Q, Zhou J, Zurth K, Caugant DA, Feavers IM, Achtman M, Spratt BG (1998) Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms. Proc Natl Acad Sci U S A 95(6):3140–3145
Marra AR, Edmond MB, Ford BA, Herwaldt LA, Algwizani AR, Diekema DJ (2017) Failure of risk-adjustment by test method for C. difficile laboratory-identified event reporting. Infect Control Hosp Epidemiol 38(1):109–111. https://doi.org/10.1017/ice.2016.227
McFarland LV, Coyle MB, Kremer WH, Stamm WE (1987) Rectal swab cultures for Clostridium difficile surveillance studies. J Clin Microbiol 25(11):2241–2242
Moehring RW, Lofgren ET, Anderson DJ (2013) Impact of change to molecular testing for Clostridium difficile infection on healthcare facilityassociated incidence rates. Infect Control Hosp Epidemiol 34(10):1055–1061. https://doi.org/10.1086/673144
Peretz A, Tkhawkho L, Pastukh N, Brodsky D, Halevi CN, Nitzan O (2016) Correlation between fecal calprotectin levels, disease severity and the hypervirulent ribotype 027 strain in patients with Clostridium difficile infection. BMC Infect Dis 16:309. https://doi.org/10.1186/s12879-016-1618-8
Planche T, Wilcox M (2011) Reference assays for Clostridium difficile infection: one or two gold standards? J Clin Pathol 64(1):1–5. https://doi.org/10.1136/jcp.2010.080135
Planche TD, Davies KA, Coen PG, Finney JM, Monahan IM, Morris KA, O’Connor L, Oakley SJ, Pope CF, Wren MW, Shetty NP, Crook DW, Wilcox MH (2013) Differences in outcome according to Clostridium difficile testing method: a prospective multicentre diagnostic validation study of C difficile infection. Lancet Infect Dis 13(11):936–945. https://doi.org/10.1016/s1473-3099(13)70200-7
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 Intern Med 175(11):1792–1801. https://doi.org/10.1001/jamainternmed.2015.4114
Popiel KY, Gheorghe R, Eastmond J, Miller MA (2015) Usefulness of adjunctive fecal calprotectin and serum procalcitonin in individuals positive for Clostridium difficile toxin gene by PCR assay. J Clin Microbiol 53(11):3667–3669. https://doi.org/10.1128/jcm.02230-15
Pressly KB, Hill E, Shah KJ (2016) Pseudomembranous colitis secondary to methicillin-resistant Staphylococcus aureus (MRSA). BMJ Case Rep 2016. https://doi.org/10.1136/bcr-2016-215225
Reddymasu S, Sheth A, Banks DE (2006) Is fecal leukocyte test a good predictor of Clostridium difficile associated diarrhea? Ann Clin Microbiol Antimicrob 5:9. https://doi.org/10.1186/1476-0711-5-9
Reigadas E, Alcala L, Marin M, Burillo A, Munoz P, Bouza E (2015) Missed diagnosis of Clostridium difficile infection; a prospective evaluation of unselected stool samples. J Inf Secur 70(3):264–272. https://doi.org/10.1016/j.jinf.2014.10.013
Reigadas E, Alcala L, Valerio M, Marin M, Martin A, Bouza E (2016) Toxin B PCR cycle threshold as a predictor of poor outcome of Clostridium difficile infection: a derivation and validation cohort study. J Antimicrob Chemother 71(5):1380–1385. https://doi.org/10.1093/jac/dkv497
Rogers DS, Kundrapu S, Sunkesula VC, Donskey CJ (2013) Comparison of perirectal versus rectal swabs for detection of asymptomatic carriers of toxigenic Clostridium difficile. J Clin Microbiol 51(10):3421–3422. https://doi.org/10.1128/JCM.01418-13
Savola KL, Baron EJ, Tompkins LS, Passaro DJ (2001) Fecal leukocyte stain has diagnostic value for outpatients but not inpatients. J Clin Microbiol 39(1):266–269. https://doi.org/10.1128/jcm.39.1.266-269.2001
Schutze GE, Willoughby RE (2013) Clostridium difficile infection in infants and children. Pediatrics 131(1):196–200. https://doi.org/10.1542/peds.2012-2992
Senchyna F, Gaur RL, Gombar S, Truong CY, Schroeder LF, Banaei N (2017) Clostridium difficile PCR cycle threshold predicts free toxin. J Clin Microbiol 55(9):2651–2660. https://doi.org/10.1128/jcm.00563-17
Sethi AK, Al-Nassir WN, Nerandzic MM, Bobulsky GS, Donskey CJ (2010) Persistence of skin contamination and environmental shedding of Clostridium difficile during and after treatment of C. difficile infection. Infect Control Hosp Epidemiol 31(1):21–27. https://doi.org/10.1086/649016
Stubbs SL, Brazier JS, O'Neill GL, Duerden BI (1999) PCR targeted to the 16S-23S rRNA gene intergenic spacer region of Clostridium difficile and construction of a library consisting of 116 different PCR ribotypes. J Clin Microbiol 37(2):461–463
Sundar S, Chan SY (2003) Cholestatic jaundice and pseudomembranous colitis following combination therapy with doxorubicin and docetaxel. Anti-Cancer Drugs 14(4):327–329. https://doi.org/10.1097/01.cad.0000065044.82984.ae
Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, McFarland LV, Mellow M, Zuckerbraun BS (2013) Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 108(4):478–498. https://doi.org/10.1038/ajg.2013.4. quiz 499
Swale A, Miyajima F, Roberts P, Hall A, Little M, Beadsworth MB, Beeching NJ, Kolamunnage-Dona R, Parry CM, Pirmohamed M (2014) Calprotectin and lactoferrin faecal levels in patients with Clostridium difficile infection (CDI): a prospective cohort study. PLoS One 9(8):e106118. https://doi.org/10.1371/journal.pone.0106118
Tang DM, Urrunaga NH, von Rosenvinge EC (2016) Pseudomembranous colitis: not always Clostridium difficile. Cleve Clin J Med 83(5):361–366. https://doi.org/10.3949/ccjm.83a.14183
Usacheva EA, Jin JP, Peterson LR (2016) Host response to Clostridium difficile infection: diagnostics and detection. J Glob Antimicrob Resist 7:93–101. https://doi.org/10.1016/j.jgar.2016.08.002
van den Berg RJ, Schaap I, Templeton KE, Klaassen CH, Kuijper EJ (2007) Typing and subtyping of Clostridium difficile isolates by using multiple-locus variable-number tandem-repeat analysis. J Clin Microbiol 45(3):1024–1028. https://doi.org/10.1128/jcm.02023-06
van Prehn J, Vandenbroucke-Grauls CM, van Beurden YH, van Houdt R, Vainio S, Ang CW (2015) Diagnostic yield of repeat sampling with immunoassay, real-time PCR, and toxigenic culture for the detection of toxigenic Clostridium difficile in an epidemic and a non-epidemic setting. Eur J Clin Microbiol Infect Dis 34(12):2325–2330. https://doi.org/10.1007/s10096-015-2484-9
Vrabie R, Kane S (2014) Noninvasive markers of disease activity in inflammatory bowel disease. Gastroenterol Hepatol 10(9):576–584
Wang T, Matukas L, Streutker CJ (2013) Histologic findings and clinical characteristics in acutely symptomatic ulcerative colitis patients with superimposed Clostridium difficile infection. Am J Clin Pathol 140(6):831–837. https://doi.org/10.1309/ajcp2lbrttjbf3kd
Wenisch C, Parschalk B, Hasenhundl M, Hirschl AM, Graninger W (1996) Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis 22(5):813–818
Whitehead SJ, Shipman KE, Cooper M, Ford C, Gama R (2014) Is there any value in measuring faecal calprotectin in Clostridium difficile positive faecal samples? J Med Microbiol 63(Pt 4):590–593. https://doi.org/10.1099/jmm.0.067389-0
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG
About this chapter
Cite this chapter
Crobach, M.J.T., Baktash, A., Duszenko, N., Kuijper, E.J. (2018). Diagnostic Guidance for C. difficile Infections. In: Mastrantonio, P., Rupnik, M. (eds) Updates on Clostridium difficile in Europe. Advances in Experimental Medicine and Biology(), vol 1050. Springer, Cham. https://doi.org/10.1007/978-3-319-72799-8_3
Download citation
DOI: https://doi.org/10.1007/978-3-319-72799-8_3
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-72798-1
Online ISBN: 978-3-319-72799-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)