Skip to main content
Top
Published in: European Journal of Clinical Microbiology & Infectious Diseases 12/2013

Open Access 01-12-2013 | Article

Elevated lactoferrin is associated with moderate to severe Clostridium difficile disease, stool toxin, and 027 infection

Authors: J. H. Boone, J. R. DiPersio, M. J. Tan, S.-J. Salstrom, K. N. Wickham, R. J. Carman, H. R. Totty, R. E. Albert, D. M. Lyerly

Published in: European Journal of Clinical Microbiology & Infectious Diseases | Issue 12/2013

Login to get access

Abstract

We evaluated blood and fecal biomarkers as indicators of severity in symptomatic patients with confirmed Clostridium difficile infection (CDI). Recruitment included patients with CDI based on clinical symptoms and supporting laboratory findings. Disease severity was defined by physician’s assessment and blood and fecal biomarkers were measured. Toxigenic culture done using spore enrichment and toxin B detected by tissue culture were done as confirmatory tests. Polymerase chain reaction (PCR) ribotyping was performed on each isolate. There were 98 patients recruited, with 85 (87 %) confirmed cases of toxigenic CDI (21 severe, 57 moderate, and seven mild), of which 68 (80 %) were also stool toxin-positive. Elevated lactoferrin (p = 0.01), increased white blood cell (WBC) count (p = 0.08), and low serum albumin (p = 0.03) were all associated with the more severe cases of CDI. Ribotype 027 infection accounted for 71 % of severe cases (p < 0.01) and patients with stool toxin had significantly higher lactoferrin levels and WBC counts (p < 0.05). Our findings show that elevated fecal lactoferrin, along with increased WBC count and low serum albumin, were associated with more severe CDI. In addition, patients infected with ribotype 027 and those with stool toxin had significantly higher fecal lactoferrin and WBC counts.
Literature
1.
go back to reference Archbald-Pannone L, Sevilleja JE, Guerrant R (2010) Diarrhea, Clostridium difficile, and intestinal inflammation in residents of a long-term care facility. J Am Med Dir Assoc 11(4):263–267PubMedCrossRef Archbald-Pannone L, Sevilleja JE, Guerrant R (2010) Diarrhea, Clostridium difficile, and intestinal inflammation in residents of a long-term care facility. J Am Med Dir Assoc 11(4):263–267PubMedCrossRef
2.
go back to reference Bartlett JG, Perl TM (2005) The new Clostridium difficile—what does it mean? N Engl J Med 353:2503–2505PubMedCrossRef Bartlett JG, Perl TM (2005) The new Clostridium difficile—what does it mean? N Engl J Med 353:2503–2505PubMedCrossRef
3.
go back to reference Barbut F, Rupnik M (2012) Editorial commentary: 027, 078, and others: going beyond the numbers (and away from the hypervirulence). Clin Infect Dis 55(12):1669–1672PubMedCrossRef Barbut F, Rupnik M (2012) Editorial commentary: 027, 078, and others: going beyond the numbers (and away from the hypervirulence). Clin Infect Dis 55(12):1669–1672PubMedCrossRef
4.
go back to reference Boone JH, Goodykoontz M, Rhodes SJ, Price K, Smith J, Gearhart KN et al (2012) Clostridium difficile prevalence rates in a large healthcare system stratified according to patient population, age, gender, and specimen consistency. Eur J Clin Microbiol Infect Dis 31(7):1551–1559PubMedCrossRef Boone JH, Goodykoontz M, Rhodes SJ, Price K, Smith J, Gearhart KN et al (2012) Clostridium difficile prevalence rates in a large healthcare system stratified according to patient population, age, gender, and specimen consistency. Eur J Clin Microbiol Infect Dis 31(7):1551–1559PubMedCrossRef
5.
go back to reference Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC et al (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):431–455PubMedCrossRef Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC et al (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):431–455PubMedCrossRef
6.
go back to reference Drudy D, Kyne L, O’Mahony R, Fanning S (2007) gyrA mutations in fluoroquinolone-resistant Clostridium difficile PCR-027. Emerg Infect Dis 13:504–505PubMedCrossRef Drudy D, Kyne L, O’Mahony R, Fanning S (2007) gyrA mutations in fluoroquinolone-resistant Clostridium difficile PCR-027. Emerg Infect Dis 13:504–505PubMedCrossRef
7.
go back to reference Eyre DW, Walker AS, Wyllie D, Dingle KE, Griffiths D, Finney J, et al (2012) Predictors of first recurrence of Clostridium difficile infection: implications for initial management. Clin Infect Dis 55:S77–S87PubMedCrossRef Eyre DW, Walker AS, Wyllie D, Dingle KE, Griffiths D, Finney J, et al (2012) Predictors of first recurrence of Clostridium difficile infection: implications for initial management. Clin Infect Dis 55:S77–S87PubMedCrossRef
8.
go back to reference Ghantoji SS, Sail K, Lairson DR, Dupont HL, Garey KW (2010) Economic healthcare costs of Clostridium difficile infection: a systematic review. J Hosp Infect 74:309–318PubMedCrossRef Ghantoji SS, Sail K, Lairson DR, Dupont HL, Garey KW (2010) Economic healthcare costs of Clostridium difficile infection: a systematic review. J Hosp Infect 74:309–318PubMedCrossRef
9.
go back to reference Guerrant RL, Araujo V, Soares E, Kotloff K, Lima AA, Cooper WH et al (1992) Measurement of fecal lactoferrin as a marker of fecal leukocytes. J Clin Microbiol 30:1238–1242PubMed Guerrant RL, Araujo V, Soares E, Kotloff K, Lima AA, Cooper WH et al (1992) Measurement of fecal lactoferrin as a marker of fecal leukocytes. J Clin Microbiol 30:1238–1242PubMed
10.
go back to reference Hubert B, Loo VG, Bourgault AM, Poirier L, Dascal A, Fortin E et al (2007) A portrait of the geographic dissemination of the Clostridium difficile North American pulsed-field type 1 strain and the epidemiology of C. difficile-associated disease in Québec. Clin Infect Dis 44:238–244PubMedCrossRef Hubert B, Loo VG, Bourgault AM, Poirier L, Dascal A, Fortin E et al (2007) A portrait of the geographic dissemination of the Clostridium difficile North American pulsed-field type 1 strain and the epidemiology of C. difficile-associated disease in Québec. Clin Infect Dis 44:238–244PubMedCrossRef
11.
go back to reference Kane SV, Sandborn WJ, Rufo PA, Zholudev A, Boone J, Lyerly D et al (2003) Fecal lactoferrin is a sensitive and specific marker in identifying intestinal inflammation. Am J Gastroenterol 98(6):1309–1314PubMedCrossRef Kane SV, Sandborn WJ, Rufo PA, Zholudev A, Boone J, Lyerly D et al (2003) Fecal lactoferrin is a sensitive and specific marker in identifying intestinal inflammation. Am J Gastroenterol 98(6):1309–1314PubMedCrossRef
12.
go back to reference Kazakova SV, Ware K, Baughman B, Bilukha O, Paradis A, Sears S et al (2006) A hospital outbreak of diarrhea due to an emerging epidemic strain of Clostridium difficile. Arch Intern Med 166:2518–2524PubMedCrossRef Kazakova SV, Ware K, Baughman B, Bilukha O, Paradis A, Sears S et al (2006) A hospital outbreak of diarrhea due to an emerging epidemic strain of Clostridium difficile. Arch Intern Med 166:2518–2524PubMedCrossRef
13.
go back to reference Kelly CP, Loo VG (eds) (2008) Current concepts in Clostridium difficile infection: a focus on severe disease. CME Newsl vol 2, issue 2, pp 1–6 Kelly CP, Loo VG (eds) (2008) Current concepts in Clostridium difficile infection: a focus on severe disease. CME Newsl vol 2, issue 2, pp 1–6
14.
go back to reference Kim H, Rhee SH, Pothoulakis C, LaMont JT (2007) Inflammation and apoptosis in Clostridium difficile enteritis is mediated by PGE2 up-regulation of Fas ligand. Gastroenterology 133:875–886PubMedCrossRef Kim H, Rhee SH, Pothoulakis C, LaMont JT (2007) Inflammation and apoptosis in Clostridium difficile enteritis is mediated by PGE2 up-regulation of Fas ligand. Gastroenterology 133:875–886PubMedCrossRef
15.
go back to reference Koo HL, Ajami NJ, Jiang ZD, Dupont HL, Atmar RL, Lewis D et al (2009) A nosocomial outbreak of norovirus infection masquerading as Clostridium difficile infection. Clin Infect Dis 48:e75–e77PubMedCrossRef Koo HL, Ajami NJ, Jiang ZD, Dupont HL, Atmar RL, Lewis D et al (2009) A nosocomial outbreak of norovirus infection masquerading as Clostridium difficile infection. Clin Infect Dis 48:e75–e77PubMedCrossRef
16.
go back to reference Langhorst J, Boone J (2012) Fecal lactoferrin as a noninvasive biomarker in inflammatory bowel diseases. Drugs Today (Barc) 48(2):149–161 Langhorst J, Boone J (2012) Fecal lactoferrin as a noninvasive biomarker in inflammatory bowel diseases. Drugs Today (Barc) 48(2):149–161
17.
go back to reference 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):311–313PubMedCrossRef 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):311–313PubMedCrossRef
18.
go back to reference Leffler DA, Lamont JT (2009) Treatment of Clostridium difficile-associated disease. Gastroenterology 136:1899–1912PubMedCrossRef Leffler DA, Lamont JT (2009) Treatment of Clostridium difficile-associated disease. Gastroenterology 136:1899–1912PubMedCrossRef
19.
go back to reference Lewis SJ, Heaton KW (1997) Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 32(9):920–924PubMedCrossRef Lewis SJ, Heaton KW (1997) Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 32(9):920–924PubMedCrossRef
20.
go back to reference Linevsky JK, Pothoulakis C, Keates S, Warny M, Keates AC, Lamont JT et al (1997) IL-8 release and neutrophil activation by Clostridium difficile toxin-exposed human monocytes. Am J Physiol 273:G1333–G1340PubMed Linevsky JK, Pothoulakis C, Keates S, Warny M, Keates AC, Lamont JT et al (1997) IL-8 release and neutrophil activation by Clostridium difficile toxin-exposed human monocytes. Am J Physiol 273:G1333–G1340PubMed
21.
go back to reference Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S et al (2005) A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 352:2442–2449CrossRef Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S et al (2005) A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 352:2442–2449CrossRef
22.
go back to reference McDonald LC, Killgore GE, Thompson A, Owens RC Jr, Kazakova SV, Sambol SP et al (2005) An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 353:2433–2441PubMedCrossRef McDonald LC, Killgore GE, Thompson A, Owens RC Jr, Kazakova SV, Sambol SP et al (2005) An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 353:2433–2441PubMedCrossRef
23.
go back to reference Morgan OW, Rodrigues B, Elston T, Verlander NQ, Brown DF, Brazier J et al (2008) Clinical severity of Clostridium difficile PCR ribotype 027: a case–case study. PLoS One 3:e1812PubMedCrossRef Morgan OW, Rodrigues B, Elston T, Verlander NQ, Brown DF, Brazier J et al (2008) Clinical severity of Clostridium difficile PCR ribotype 027: a case–case study. PLoS One 3:e1812PubMedCrossRef
24.
go back to reference O’Brien JA, Lahue BJ, Caro JJ, Davidson DM (2007) The emerging infectious challenge of Clostridium difficile-associated disease in Massachusetts hospitals: clinical and economic consequences. Infect Control Hosp Epidemiol 28:1219–1227PubMedCrossRef O’Brien JA, Lahue BJ, Caro JJ, Davidson DM (2007) The emerging infectious challenge of Clostridium difficile-associated disease in Massachusetts hospitals: clinical and economic consequences. Infect Control Hosp Epidemiol 28:1219–1227PubMedCrossRef
25.
go back to reference Pawlowski SW, Archbald-Pannone L, Carman RJ, Alcantara-Warren C, Lyerly D, Genheimer CW et al (2009) Elevated levels of intestinal inflammation in Clostridium difficile infection associated with fluoroquinolone-resistant C. difficile. J Hosp Infect 73(2):185–187PubMedCrossRef Pawlowski SW, Archbald-Pannone L, Carman RJ, Alcantara-Warren C, Lyerly D, Genheimer CW et al (2009) Elevated levels of intestinal inflammation in Clostridium difficile infection associated with fluoroquinolone-resistant C. difficile. J Hosp Infect 73(2):185–187PubMedCrossRef
26.
go back to reference Pépin J, Valiquette L, Cossette B (2005) Mortality attributable to nosocomial Clostridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ 173(9):1037–1042. doi:10.1503/cmaj.050978 PubMedCrossRef Pépin J, Valiquette L, Cossette B (2005) Mortality attributable to nosocomial Clostridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ 173(9):1037–1042. doi:10.​1503/​cmaj.​050978 PubMedCrossRef
27.
go back to reference Planche TD, Davies KA, Coen PG, Crook D, Shetty N, Wren M et al (2012) Clinical validation of Clostridium difficile infection (CDI) diagnostics: importance of toxin detection. In: Proceedings of the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, CA, September 2012 Planche TD, Davies KA, Coen PG, Crook D, Shetty N, Wren M et al (2012) Clinical validation of Clostridium difficile infection (CDI) diagnostics: importance of toxin detection. In: Proceedings of the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, CA, September 2012
28.
go back to reference Pothoulakis C, Sullivan R, Melnick DA, Triadafilopoulos G, Gadenne AS, Meshulam T et al (1988) Clostridium difficile toxin A stimulates intracellular calcium release and chemotactic response in human granulocytes. J Clin Invest 81:1741–1745PubMedCrossRef Pothoulakis C, Sullivan R, Melnick DA, Triadafilopoulos G, Gadenne AS, Meshulam T et al (1988) Clostridium difficile toxin A stimulates intracellular calcium release and chemotactic response in human granulocytes. J Clin Invest 81:1741–1745PubMedCrossRef
29.
go back to reference Savidge TC, Pan WH, Newman P, O’Brien M, Anton PM, Pothoulakis C (2003) Clostridium difficile toxin B is an inflammatory enterotoxin in human intestine. Gastroenterology 125:413–420PubMedCrossRef Savidge TC, Pan WH, Newman P, O’Brien M, Anton PM, Pothoulakis C (2003) Clostridium difficile toxin B is an inflammatory enterotoxin in human intestine. Gastroenterology 125:413–420PubMedCrossRef
30.
go back to reference Schoepfer AM, Trummler M, Seeholzer P, Seibold-Schmid B, Seibold F (2008) Discriminating IBD from IBS: comparison of the test performance of fecal markers, blood leukocytes, CRP, and IBD antibodies. Inflamm Bowel Dis 14:32–39PubMedCrossRef Schoepfer AM, Trummler M, Seeholzer P, Seibold-Schmid B, Seibold F (2008) Discriminating IBD from IBS: comparison of the test performance of fecal markers, blood leukocytes, CRP, and IBD antibodies. Inflamm Bowel Dis 14:32–39PubMedCrossRef
31.
go back to reference Sipponen T, Savilahti E, Kärkkäinen P, Kolho KL, Nuutinen H, Turunen U et al (2008) Fecal calprotectin, lactoferrin, and endoscopic disease activity in monitoring anti-TNF-alpha therapy for Crohn’s disease. Inflamm Bowel Dis 14(10):1392–1398PubMedCrossRef Sipponen T, Savilahti E, Kärkkäinen P, Kolho KL, Nuutinen H, Turunen U et al (2008) Fecal calprotectin, lactoferrin, and endoscopic disease activity in monitoring anti-TNF-alpha therapy for Crohn’s disease. Inflamm Bowel Dis 14(10):1392–1398PubMedCrossRef
32.
go back to reference Sipponen T, Savilahti E, Kolho KL, Nuutinen H, Turunen U, Färkkilä M (2007) Crohn’s disease activity assessed by fecal calprotectin and lactoferrin: correlation with Crohn’s disease activity index and endoscopic findings. Inflamm Bowel Dis 14:40–46CrossRef Sipponen T, Savilahti E, Kolho KL, Nuutinen H, Turunen U, Färkkilä M (2007) Crohn’s disease activity assessed by fecal calprotectin and lactoferrin: correlation with Crohn’s disease activity index and endoscopic findings. Inflamm Bowel Dis 14:40–46CrossRef
33.
go back to reference 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 37:461–463PubMed 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 37:461–463PubMed
34.
go back to reference Sugi K, Saitoh O, Hirata I, Katsu K (1996) Fecal lactoferrin as a marker for disease activity in inflammatory bowel disease: comparison with other neutrophil-derived proteins. Am J Gastroenterol 91(5):927–934PubMed Sugi K, Saitoh O, Hirata I, Katsu K (1996) Fecal lactoferrin as a marker for disease activity in inflammatory bowel disease: comparison with other neutrophil-derived proteins. Am J Gastroenterol 91(5):927–934PubMed
35.
36.
go back to reference Tan ET, Robertson CA, Brynildsen S, Bresnitz E, Tan C, McDonald C (2007) Clostridium difficile-associated disease in New Jersey hospitals, 2000–2004. Emerg Infect Dis 13:498–500PubMedCrossRef Tan ET, Robertson CA, Brynildsen S, Bresnitz E, Tan C, McDonald C (2007) Clostridium difficile-associated disease in New Jersey hospitals, 2000–2004. Emerg Infect Dis 13:498–500PubMedCrossRef
37.
go back to reference Walk ST, Micic D, Jain R, Lo ES, Trivedi I, Liu EW et al (2012) Clostridium difficile ribotype does not predict severe infection. Clin Infect Dis 55(12):1661–1668PubMedCrossRef Walk ST, Micic D, Jain R, Lo ES, Trivedi I, Liu EW et al (2012) Clostridium difficile ribotype does not predict severe infection. Clin Infect Dis 55(12):1661–1668PubMedCrossRef
38.
go back to reference Walker TR, Land ML, Kartashov A, Saslowsky TM, Lyerly DM, Boone JH et al (2007) Fecal lactoferrin is a sensitive and specific marker of disease activity in children and young adults with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 44:414–422PubMedCrossRef Walker TR, Land ML, Kartashov A, Saslowsky TM, Lyerly DM, Boone JH et al (2007) Fecal lactoferrin is a sensitive and specific marker of disease activity in children and young adults with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 44:414–422PubMedCrossRef
39.
go back to reference Wren MW, Kinson R, Sivapalan M, Shemko M, Shetty NR (2009) Detection of Clostridium difficile infection: a suggested laboratory diagnostic algorithm. Br J Biomed Sci 66(4):175–179PubMed Wren MW, Kinson R, Sivapalan M, Shemko M, Shetty NR (2009) Detection of Clostridium difficile infection: a suggested laboratory diagnostic algorithm. Br J Biomed Sci 66(4):175–179PubMed
40.
go back to reference Zar FA, Bakkanagari SR, Moorthi KM, Davis MB (2007) A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 45:302–307PubMedCrossRef Zar FA, Bakkanagari SR, Moorthi KM, Davis MB (2007) A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 45:302–307PubMedCrossRef
Metadata
Title
Elevated lactoferrin is associated with moderate to severe Clostridium difficile disease, stool toxin, and 027 infection
Authors
J. H. Boone
J. R. DiPersio
M. J. Tan
S.-J. Salstrom
K. N. Wickham
R. J. Carman
H. R. Totty
R. E. Albert
D. M. Lyerly
Publication date
01-12-2013
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Clinical Microbiology & Infectious Diseases / Issue 12/2013
Print ISSN: 0934-9723
Electronic ISSN: 1435-4373
DOI
https://doi.org/10.1007/s10096-013-1905-x

Other articles of this Issue 12/2013

European Journal of Clinical Microbiology & Infectious Diseases 12/2013 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.