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Predictive value of fecal calprotectin and lactoferrin levels for negative outcomes in Clostridioides difficile infection

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European Journal of Clinical Microbiology & Infectious Diseases Aims and scope Submit manuscript

Abstract

Purpose

We investigated the role of fecal calprotectin (FC) and lactoferrin (FL) as predictive biomarkers in Clostridioides difficile infection (CDI).

Methods

We assembled a prospective cohort including all patients with a laboratory-confirmed CDI diagnosis between January and December 2017. FL and FC levels were measured at diagnosis by commercial ELISA and EIA kits. We investigated the diagnostic accuracy of FC and FL to predict CDI recurrence and severity (study outcomes) and explored optimal cut-off values in addition to those proposed by the manufacturers (200 µg/g and 7.2 µg/mL, respectively).

Results

We included 170 CDI cases (152 first episodes and 18 recurrences). The rates of recurrence (first episodes only) and severity (entire cohort) were 9.2% (14/152) and 46.5% (79/170). Both FL and FC levels were significantly higher in patients who developed study outcomes. Optimal cut-off values for FC and FL to predict CDI recurrence were 1052 µg/g and 6.0 µg/mL. The optimal cut-off value for FC yielded higher specificity (60.9%) and positive predictive value (PPV) (16.9%) than that proposed by the manufacturer. Regarding CDI severity, the optimal cut-off value for FC (439 µg/g) also provided higher specificity (43.9%) and PPV (54.1%) than that of the manufacturer, whereas the optimal cut-off value for FL (4.6 µg/mL) resulted in an improvement of PPV (57.5%).

Conclusion

By modifying the thresholds for assay positivity, the measurement of FC and FL at diagnosis is useful to predict recurrence and severity in CDI. Adding these biomarkers to current clinical scores may help to individualize CDI management.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

aOR:

Adjusted odds ratio

auROC:

Area under the receiver operator characteristic curve

CCI:

Charlson comorbidity index

CDI:

Clostridioides difficile Infection

CI:

Confidence interval

ED:

Emergency department

EIA:

Enzyme immunoassay

ELISA:

Enzyme-linked immunosorbent assay

FDA:

Food and Drug Administration

GDH:

Glutamate dehydrogenase

HCFA:

Healthcare facility–associated

IBD:

Inflammatory bowel disease

IQR:

Interquartile range

IV:

Intravenous

NNAT:

Nucleic acid amplification testing

NPV:

Negative predictive value

PPI:

Proton-pump inhibitors

PPV:

Positive predictive value

SD:

Standard deviation

SOT:

Solid organ transplantation

WBC:

White blood cell count

References

  1. Schaffler H, Breitruck A (2018) Clostridium difficile - from colonization to infection. Front Microbiol 9:646

    Article  PubMed  PubMed Central  Google Scholar 

  2. Moore SC (2018) Clostridium difficile: more challenging than ever. Crit Care Nurs Clin North Am 30(1):41–53

    Article  PubMed  Google Scholar 

  3. Bouza E, Cobo J, Almirante B, Grupo de Trabajo C (2019) Recommendations from a panel of experts on the usefulness of fidaxomicin for the treatment of infections caused by Clostridium difficile. Rev Esp Quimioter 32(1):50–9

    PubMed  PubMed Central  CAS  Google Scholar 

  4. Song JH, Kim YS (2019) Recurrent Clostridium difficile infection: risk factors, treatment, and prevention. Gut Liver 13(1):16–24

    Article  PubMed  CAS  Google Scholar 

  5. Esteban-Vasallo MD, de Miguel-Diez J, Lopez-de-Andres A, Hernandez-Barrera V, Jimenez-Garcia R (2019) Clostridium difficile-related hospitalizations and risk factors for in-hospital mortality in Spain between 2001 and 2015. J Hosp Infect 102(2):148–156

    Article  PubMed  CAS  Google Scholar 

  6. Kelly CP (2012) Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol Infect 18(Suppl 6):21–27

    Article  PubMed  Google Scholar 

  7. Barbut F, Richard A, Hamadi K, Chomette V, Burghoffer B, Petit JC (2000) Epidemiology of recurrences or reinfections of Clostridium difficile-associated diarrhea. J Clin Microbiol 38(6):2386–2388

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Johnson S, Lavergne V, Skinner AM et al (2021) Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults. Clin Infect Dis 73(5):755–757

    Article  PubMed  Google Scholar 

  9. van Prehn J, Reigadas E, Vogelzang EH et al (2021) European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults. Clin Microbiol Infect 27(Suppl 2):S1–S21

    Article  PubMed  Google Scholar 

  10. Reigadas E, van Prehn J, Falcone M et al (2021) How to: prophylactic interventions for prevention of Clostridioides difficile infection. Clin Microbiol Infect 27(12):1777–1783

    Article  PubMed  Google Scholar 

  11. Barbut F, Gouot C, Lapidus N et al (2017) Faecal lactoferrin and calprotectin in patients with Clostridium difficile infection: a case-control study. Eur J Clin Microbiol Infect Dis 36(12):2423–2430

    Article  PubMed  CAS  Google Scholar 

  12. Abou Chakra CN, Pepin J, Valiquette L (2012) Prediction tools for unfavourable outcomes in Clostridium difficile infection: a systematic review. PLoS ONE 7(1):e30258

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Gallo A, Vallone C, Sabatelli L et al (2018) Fecal calprotectin in management of Clostridium difficile infection: a longitudinal study. Scand J Gastroenterol 53(5):567–572

    Article  PubMed  CAS  Google Scholar 

  14. Kim J, Kim H, Oh HJ et al (2017) Fecal calprotectin level reflects the severity of Clostridium difficile infection. Ann Lab Med 37(1):53–57

    Article  PubMed  CAS  Google Scholar 

  15. Boone JH, DiPersio JR, Tan MJ et al (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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Wen BJ, Te LG, Liu XX, Zhao JH (2022) The value of fecal calprotectin in Clostridioides difficile infection: a systematic review. Front Physiol 13:881816

    Article  PubMed  PubMed Central  Google Scholar 

  17. Origuen J, Corbella L, Orellana MA et al (2018) Comparison of the clinical course of Clostridium difficile infection in glutamate dehydrogenase-positive toxin-negative patients diagnosed by PCR to those with a positive toxin test. Clin Microbiol Infect 24(4):414–421

    Article  PubMed  CAS  Google Scholar 

  18. Origuen J, Orellana MA, Fernandez-Ruiz M et al (2019) Toxin B PCR amplification cycle threshold adds little to clinical variables for predicting outcomes in Clostridium difficile infection: a retrospective cohort study. J Clin Microbiol 57(2):e01125-18

  19. Bagdasarian N, Rao K, Malani PN (2015) Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA 313(4):398–408

    Article  PubMed  PubMed Central  Google Scholar 

  20. McDonald LC, Gerding DN, Johnson S et al (2018) Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 66(7):987–994

    Article  PubMed  CAS  Google Scholar 

  21. Cohen SH, Gerding DN, Johnson S 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):431–455

    Article  PubMed  Google Scholar 

  22. Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40(5):373–383

    Article  PubMed  CAS  Google Scholar 

  23. Orellana-Miguel MA, Alcolea-Medina A, Barrado-Blanco L, Rodriguez-Otero J, Chaves-Sanchez F (2013) Algorithm proposal based on the C. Diff Quik Chek Complete ICT device for detecting Clostridium difficile infection. Enferm Infecc Microbiol Clin 31(2):97–99

  24. Youden WJ (1950) Index for rating diagnostic tests. Cancer 3(1):32–35

    Article  PubMed  CAS  Google Scholar 

  25. Brandtzaeg P, Gabrielsen TO, Dale I, Muller F, Steinbakk M, Fagerhol MK (1995) The leucocyte protein L1 (calprotectin): a putative nonspecific defence factor at epithelial surfaces. Adv Exp Med Biol 371A:201–206

    Article  PubMed  CAS  Google Scholar 

  26. Sanchez L, Calvo M, Brock JH (1992) Biological role of lactoferrin. Arch Dis Child 67(5):657–661

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. 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(3):302–307

    Article  PubMed  CAS  Google Scholar 

  28. Perry DA, Shirley D, Micic D et al (2022) External validation and comparison of Clostridioides difficile severity scoring systems. Clin Infect Dis 74(11):2028–2035

    Article  PubMed  Google Scholar 

  29. Swale A, Miyajima F, Roberts P et al (2014) Calprotectin and lactoferrin faecal levels in patients with Clostridium difficile infection (CDI): a prospective cohort study. PLoS ONE 9(8):e106118

    Article  PubMed  PubMed Central  Google Scholar 

  30. Suarez-Carantona C, Rodriguez-Torres A, Viteri-Noel A et al (2021) Usefulness of fecal calprotectin in the management of patients with toxigenic Clostridioides difficile. J Clin Med 10(8):1627

  31. Rao K, Malani PN (2020) Diagnosis and treatment of Clostridioides (Clostridium) difficile infection in adults in 2020. JAMA 323(14):1403–1404

    Article  PubMed  Google Scholar 

  32. Ofori E, Ramai D, Dhawan M, Mustafa F, Gasperino J, Reddy M (2018) Community-acquired Clostridium difficile: epidemiology, ribotype, risk factors, hospital and intensive care unit outcomes, and current and emerging therapies. J Hosp Infect 99(4):436–442

    Article  PubMed  CAS  Google Scholar 

  33. Ooijevaar RE, van Beurden YH, Terveer EM et al (2018) Update of treatment algorithms for Clostridium difficile infection. Clin Microbiol Infect 24(5):452–462

    Article  PubMed  CAS  Google Scholar 

  34. 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

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gateau C, Couturier J, Coia J, Barbut F (2018) How to: diagnose infection caused by Clostridium difficile. Clin Microbiol Infect 24(5):463–468

    Article  PubMed  CAS  Google Scholar 

  36. 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Wilcox MH, Gerding DN, Poxton IR et al (2017) Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med 376(4):305–317

    Article  PubMed  CAS  Google Scholar 

  38. van Nood E, Vrieze A, Nieuwdorp M et al (2013) Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 368(5):407–415

    Article  PubMed  Google Scholar 

  39. Pawlowski SW, Warren CA, Guerrant R (2009) Diagnosis and treatment of acute or persistent diarrhea. Gastroenterology 136(6):1874–1886

    Article  PubMed  CAS  Google Scholar 

  40. Nicholson MR, Crews JD, Starke JR, Jiang ZD, DuPont H, Edwards K (2017) Recurrent Clostridium difficile infection in children: patient risk factors and markers of intestinal inflammation. Pediatr Infect Dis J 36(4):379–383

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study has been funded by an unrestricted grant from Merck Sharp & Dohme (MSD) and by Instituto de Salud Carlos III (ISCIII)—co-funded by the European Regional Development Fund / European Social Fund “A way to make Europe / Investing in your future”). M.F.R. holds a research contract “Miguel Servet” (CP18/00073) from the ISCIII, Spanish Ministry of Science and Innovation, also co-funded by the European Union. Funding sources had no involvement in the study design and conduction, data analysis, or manuscript preparation.

Author information

Authors and Affiliations

  1. Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital, 12 de Octubre” (imas12), Madrid, Spain

    Mario Ágreda Fernández, Julia Origüen, Isabel Rodriguez-Goncer, Rafael San Juan, Francisco López-Medrano, Patricia Parra, Tamara Ruiz-Merlo, Natalia Redondo, José María Aguado & Mario Fernández-Ruiz

  2. Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain

    Rafael San Juan, Francisco López-Medrano, Natalia Redondo, José María Aguado & Mario Fernández-Ruiz

  3. Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain

    Rafael San Juan, Francisco López-Medrano, José María Aguado & Mario Fernández-Ruiz

  4. Department of Microbiology, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital, 12 de Octubre” (imas12), Madrid, Spain

    María Ángeles Orellana

Authors
  1. Mario Ágreda Fernández
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  2. Julia Origüen
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  4. Rafael San Juan
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  6. Patricia Parra
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  7. Tamara Ruiz-Merlo
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  8. Natalia Redondo
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  9. María Ángeles Orellana
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  10. José María Aguado
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  11. Mario Fernández-Ruiz
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Contributions

M. Á. participated in the study concept and design, data collection, and manuscript writing, drafting, and reviewing. J. O. participated in the clinical management of patients, study concept and design, data collection, and manuscript editing and reviewing. I. R.-G., R. S. J., and F. L.-M. participated in the clinical management of patients and manuscript editing and reviewing. P. P., T. R.-M., N. R., and M. Á. O. participated in the laboratory procedures and manuscript editing and reviewing. J. M. A. participated in the study concept and design, and manuscript editing and reviewing. M. F.-R. participated in the study concept and design, data analysis and interpretation, and manuscript writing, editing, and reviewing. All authors have read and approved the submitted manuscript.

Corresponding author

Correspondence to Mario Ágreda Fernández.

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Ethics approval and consent to participate

The study protocol was submitted for evaluation and approved by the Ethics and Clinical Research Committee (CEIC) of the Research Institute Hospital “12 de Octubre” (i + 12). Informed consent was signed by all participants before inclusion in the study. All information related to the study was treated as strictly confidential in accordance with Organic Law 3/2018, of December 5, on Personal Data Protection and Guarantee of Digital Rights and the Biomedical Research Law 14/2007. The study was performed in accordance with the ethical principles set out in the latest version of the Helsinki

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The authors declare no competing interests.

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Ágreda Fernández, M., Origüen, J., Rodriguez-Goncer, I. et al. Predictive value of fecal calprotectin and lactoferrin levels for negative outcomes in Clostridioides difficile infection. Eur J Clin Microbiol Infect Dis 43, 313–324 (2024). https://doi.org/10.1007/s10096-023-04729-z

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