Home Polymorphic mononuclear neutrophils CD64 index for diagnosis of sepsis in postoperative surgical patients and critically ill patients
Article
Licensed
Unlicensed Requires Authentication

Polymorphic mononuclear neutrophils CD64 index for diagnosis of sepsis in postoperative surgical patients and critically ill patients

  • Jeroen H. Gerrits EMAIL logo , Pamela M.J. McLaughlin , Bert N. Nienhuis , Jan W. Smit and Bert Loef
Published/Copyright: October 6, 2012
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 51 Issue 4

Abstract

Background: Surface neutrophil CD64 expression is upregulated in patients with bacterial infection. As it was suggested that the CD64 index could be used to detect sepsis in hospitalized patients, we questioned whether the CD64 index could discriminate between septic patients and postoperative surgical patients, defined as systemic inflammatory response syndrome (SIRS), both admitted at the intensive care unit (ICU). Furthermore, we wondered whether the CD64 index was an improved diagnostic compared to standard assays used at the laboratory. For this, outclinic (OC) patients were included as controls.

Methods: The Leuko64™ assay was used to determine the CD64 index in residual EDTA blood samples from selected septic patients (n=25), SIRS patients (n=19), and OC patients (n=24). Additionally, WBC count, neutrophilic and eosinophilic granulocyte count, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were measured simultaneously.

Results: The CD64 index was higher in septic patients compared to both the SIRS and OC group (p<0.0001). In addition, the WBC count, neutrophil count, ESR and CRP were also higher in septic patients than the OC group (p<0.0001). However, only the WBC count, eosinopenia, and ESR were comparable between the SIRS and the sepsis group and proved to be discriminative to the OC group (p<0.05). The CD64 index demonstrated higher sensitivity and specificity than CRP, WBC count, neutrophilic and eosinophilic granulocyte count, and ESR.

Conclusions: A high CD64 index was found in septic intensive care patients, while a low CD64 index was observed in OC and SIRS patients, demonstrating that the CD64 index can be used for routine diagnostics in the ICU setting.

Keywords: bacterial infection; CD64; diagnostic accuracy sepsis; intensive care unit; systemic inflammatory response syndrome
Corresponding author: Jeroen H. Gerrits, LabNoord, Clinical Chemistry Laboratory, Martini Hospital, Room 5D106, Van Swietenplein 1, 9728 NT Groningen, The Netherlands, Phone: +31 50 5247594, Fax: +31 50 5246676

The Leuko64™ assay was kindly provided by J.H.N. Schuitemaker from IQ products, the Netherlands. Furthermore, we thank R.F.M. Oude Elferink for statistical support.

Conflict of interest statement

Conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article.

Research funding: None declared.

Employment of leadership: None declared.

Honorarium: None declared.

References

1. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36:296–327.10.1097/01.CCM.0000298158.12101.41Search in Google Scholar PubMed

2. Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, Kurosawa S, Remick DG. The pathogenesis of sepsis. Annu Rev Pathol 2011;6:19–48.10.1146/annurev-pathol-011110-130327Search in Google Scholar

3. Russell JA. Management of sepsis. N Engl J Med 2006;355: 1699–713.10.1056/NEJMra043632Search in Google Scholar PubMed

4. Hoffmann JJ. Neutrophil CD64: a diagnostic marker for infection and sepsis. Clin Chem Lab Med 2009;47:903–16.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000268507800002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar

5. Chan T, Gu F. Early diagnosis of sepsis using serum biomarkers. Expert Rev Mol Diagn 2011;11:487–96.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000292420500010&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f310.1586/erm.11.26Search in Google Scholar PubMed

6. Wang P, Yang Z, He Y, Shu C. Pitfalls in the rapid diagnosis of positive blood culture. Rev Med Microbiol 2010;21:39–43.10.1097/MRM.0b013e32833bb953Search in Google Scholar

7. Carrol ED, Thomson AP, Hart CA. Procalcitonin as a marker of sepsis. Int J Antimicrob Agents 2002;20:1–9.10.1016/S0924-8579(02)00047-XSearch in Google Scholar PubMed

8. Schuerholz T, Marx G. Management of sepsis. Minerva Anestesiol 2008;74:181–95.Search in Google Scholar PubMed

9. Eissa D, Carton EG, Buggy DJ. Anaesthetic management of patients with severe sepsis. Br J Anaesth 2010;105:734–43.10.1093/bja/aeq305Search in Google Scholar PubMed

10. Abidi K, Khoudri I, Belayachi J, Madani N, Zekraoui A, Zeggwagh AA, et al. Eosinopenia is a reliable marker of sepsis on admission to medical intensive care units. Crit Care 2008;12:R59.10.1186/cc6883Search in Google Scholar PubMed PubMed Central

11. Davis BH, Olsen SH, Ahmad E, Bigelow NC. Neutrophil CD64 is an improved indicator of infection or sepsis in emergency department patients. Arch Pathol Lab Med 2006;130:654–61.10.5858/2006-130-654-NCIAIISearch in Google Scholar PubMed

12. Nuutila J, Hohenthal U, Laitinen I, Kotilainen P, Rajamaki A, Nikoskelainen J, et al. Simultaneous quantitative analysis of FcgammaRI (CD64) expression on neutrophils and monocytes: a new, improved way to detect infections. J Immunol Methods 2007;328:189–200.10.1016/j.jim.2007.09.002http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000251490900020&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed

13. Nuutila J. The novel applications of the quantitative analysis of neutrophil cell surface FcgammaRI (CD64) to the diagnosis of infectious and inflammatory diseases. Curr Opin Infect Dis 2010;23:268–74.10.1097/QCO.0b013e32833939b0http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000277800900011&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed

14. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:1250–6.10.1097/01.CCM.0000050454.01978.3BSearch in Google Scholar PubMed

15. Arnon S, Litmanovitz I. Diagnostic tests in neonatal sepsis. Curr Opin Infect Dis 2008;21:223–7.10.1097/QCO.0b013e3282fa15ddhttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000257102100002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed

16. Beekmann SE, Diekema DJ, Doern GV. Determining the clinical significance of coagulase-negative staphylococci isolated from blood cultures. Infect Control Hosp Epidemiol 2005;26:559–66.10.1086/502584Search in Google Scholar PubMed

17. Richter SS, Beekmann SE, Croco JL, Diekema DJ, Koontz FP, Pfaller MA, et al. Minimizing the workup of blood culture contaminants: implementation and evaluation of a laboratory-based algorithm. J Clin Microbiol 2002;40:2437–44.10.1128/JCM.40.7.2437-2444.2002Search in Google Scholar PubMed PubMed Central

18. Standage SW, Wong HR. Biomarkers for pediatric sepsis and septic shock. Expert Rev Anti Infect Ther 2011;9:71–9.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000288974400014&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar

19. Cid J, Aguinaco R, Sanchez R, Garcia-Pardo G, Llorente A. Neutrophil CD64 expression as marker of bacterial infection: a systematic review and meta-analysis. J Infect 2010;60:313–9.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000277203300001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f310.1016/j.jinf.2010.02.013Search in Google Scholar PubMed

20. Groselj-Grenc M, Ihan A, Pavcnik-Arnol M, Kopitar AN, Gmeiner-Stopar T, Derganc M. Neutrophil and monocyte CD64 indexes, lipopolysaccharide-binding protein, procalcitonin and C-reactive protein in sepsis of critically ill neonates and children. Intensive Care Med 2009;35:1950–8.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000271026300018&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f310.1007/s00134-009-1637-7Search in Google Scholar PubMed

21. Fjaertoft G, Hakansson LD, Pauksens K, Sisask G, Venge P. Neutrophil CD64 (FcgammaRI) expression is a specific marker of bacterial infection: a study on the kinetics and the impact of major surgery. Scand J Infect Dis 2007;39: 525–35.10.1080/00365540601113693Search in Google Scholar PubMed

22. Fischer G, Schneider EM, Moldawer LL, Karcher C, Barth E, Suger-Wiedeck H, et al. CD64 surface expression on neutrophils is transiently upregulated in patients with septic shock. Intensive Care Med 2001;27:1848–52.10.1007/s00134-001-1135-zSearch in Google Scholar PubMed

23. Icardi M, Erickson Y, Kilborn S, Stewart B, Grief B, Scharnweber G. CD64 index provides simple and predictive testing for detection and monitoring of sepsis and bacterial infection in hospital patients. J Clin Microbiol 2009;47:3914–9.10.1128/JCM.00628-09Search in Google Scholar PubMed PubMed Central

24. Davis BH, Bigelow NC. Comparison of neutrophil CD64 expression, manual myeloid immaturity counts, and automated hematology analyzer flags as indicators of infection or sepsis. Lab Hematol 2005;11:137–47.10.1532/LH96.04077Search in Google Scholar

25. Gros A, Roussel M, Sauvadet E, Gacouin A, Marque S, Chimot L, et al. The sensitivity of neutrophil CD64 expression as a biomarker of bacterial infection is low in critically ill patients. Intensive Care Med 2012;38:445–52.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000300776300012&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f310.1007/s00134-012-2483-6Search in Google Scholar

26. Mokart D, Merlin M, Sannini A, Brun JP, Delpero JR, Houvenaeghel G, et al. Procalcitonin, interleukin 6 and systemic inflammatory response syndrome (SIRS): early markers of postoperative sepsis after major surgery. Br J Anaesth 2005;94:767–73.10.1093/bja/aei143Search in Google Scholar PubMed

27. Oda S, Hirasawa H, Shiga H, Nakanishi K, Matsuda K, Nakamua M. Sequential measurement of IL-6 blood levels in patients with systemic inflammatory response syndrome (SIRS)/sepsis. Cytokine 2005;29:169–75.10.1016/j.cyto.2004.10.010Search in Google Scholar PubMed

28. Reinhart K, Meisner M. Biomarkers in the critically ill patient: procalcitonin. Crit Care Clin 2011;27:253–63.10.1016/j.ccc.2011.01.002Search in Google Scholar PubMed

29. Tang BM, Eslick GD, Craig JC, McLean AS. Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis. Lancet Infect Dis 2007;7:210–7.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000244584700019&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f310.1016/S1473-3099(07)70052-XSearch in Google Scholar PubMed

30. Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med 2008;36:941–52.10.1097/CCM.0B013E318165BABBhttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000253450500039&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed

31. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011;1813:878–88.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000291125300022&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f310.1016/j.bbamcr.2011.01.034Search in Google Scholar PubMed

32. Limper M, de Kruif MD, Duits AJ, Brandjes DP, van Gorp EC. The diagnostic role of procalcitonin and other biomarkers in discriminating infectious from non-infectious fever. J Infect 2010;60:409–16.10.1016/j.jinf.2010.03.016http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000278176200001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed

33. Osuchowski MF, Welch K, Siddiqui J, Remick DG. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol 2006;177:1967–74.10.4049/jimmunol.177.3.1967Search in Google Scholar PubMed

34. Tschaikowsky K, Hedwig-Geissing M, Braun GG, Radespiel-Troeger M. Predictive value of procalcitonin, interleukin-6, and C-reactive protein for survival in postoperative patients with severe sepsis. J Crit Care 2011;26:54–64.10.1016/j.jcrc.2010.04.011http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000287465900010&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed

Received: 2012-05-04
Accepted: 2012-08-28
Published Online: 2012-10-06
Published in Print: 2013-04-01

©2013 by Walter de Gruyter Berlin Boston

Articles in the same Issue

  1. Letters to the Editor
  2. Missing agreement between the two IMMULITE® PSA assays
  3. “Cerebrovascular stressing”: dipyridamole-induced S100B elevation predicts ischemic cerebrovascular events
  4. Discrepancy in lamellar body counts (LBCs) between the Sysmex XE-2100 and Sysmex XT-2000i instruments
  5. Interphase fluorescent in situ hybridization detection of the 7q11.23 chromosomal inversion in a clinical laboratory: automated versus manual scoring
  6. Adrenocorticotropic hormone stability in preanalytical phase depends on temperature and proteolytic enzyme inhibitor
  7. The impact on costs and efficiency of reducing the number of collected tubes
  8. Improved software on the Sysmex XE-5000 BF mode for counting leukocytes in cerebrospinal fluid
  9. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 are significantly related to PAPP-A levels
  10. Preliminary evaluation of complete blood cell count on Mindray BC-6800
  11. Rational use of laboratory tests: albuminuria
  12. Masthead
  13. Masthead
  14. Editorials
  15. Fifty years of CCLM – invitation to join us for a reception in Milan
  16. Personalized (laboratory) medicine: a bridge to the future
  17. PSA, PCA3 and the phi losophy of prostate cancer management
  18. Reviews
  19. Gender medicine: a task for the third millennium
  20. Evaluation of [−2] proPSA and Prostate Health Index (phi) for the detection of prostate cancer: a systematic review and meta-analysis
  21. Harmonization in laboratory medicine: the complete picture
  22. Opinion Papers
  23. Glycemic control in the clinical management of diabetic patients
  24. Time for a conceptual shift in assessment of internal quality control for whole blood or cell-based testing systems? An evaluation using platelet function and the PFA-100 as a case example
  25. Guidelines and Recommendations
  26. A position paper of the EFLM Committee on Education and Training and Working Group on Distance Education Programmes/E-Learning: developing an e-learning platform for the education of stakeholders in laboratory medicine
  27. General Clinical Chemistry and Laboratory Medicine
  28. A novel weighted cumulative delta-check method for highly sensitive detection of specimen mix-up in the clinical laboratory
  29. Identification and quantification of hemoglobins in whole blood: the analytical and organizational aspects of Capillarys 2 Flex Piercing compared with agarose electrophoresis and HPLC methods
  30. Determination of the fatty acid profile of neutral lipids, free fatty acids and phospholipids in human plasma
  31. Urinary iodine concentrations of pregnant women in Ukraine
  32. Delay in the measurement of eosin-5′-maleimide (EMA) binding does not affect the test result for the diagnosis of hereditary spherocytosis
  33. Faecal calprotectin: comparative study of the Quantum Blue rapid test and an established ELISA method
  34. Target analyte quantification by isotope dilution LC-MS/MS directly referring to internal standard concentrations – validation for serum cortisol measurement
  35. Reference Values and Biological Variations
  36. Reference values and upper reference limits for 26 trace elements in the urine of adults living in Belgium
  37. Biological variation and reference change values of common clinical chemistry and haematologic laboratory analytes in the elderly population
  38. Indirect determination of pediatric blood count reference intervals
  39. Cancer Diagnostics
  40. Suitability of quality control materials for prostate-specific antigen (PSA) measurement: inter-method variability of common tumor marker control materials
  41. Prostate cancer antigen 3 (PCA3) RNA detection in blood and tissue samples for prostate cancer diagnosis
  42. Serum levels of cancer biomarkers in diabetic and non-diabetic proteinuric patients: a preliminary study
  43. Infectious Diseases
  44. Polymorphic mononuclear neutrophils CD64 index for diagnosis of sepsis in postoperative surgical patients and critically ill patients
  45. Plasma long pentraxin 3 (PTX3) concentration is a novel marker of disease activity in patients with community-acquired pneumonia
https://doi.org/10.1515/cclm-2012-0279
Keywords for this article
bacterial infection; CD64; diagnostic accuracy sepsis; intensive care unit; systemic inflammatory response syndrome

Articles in the same Issue

  1. Letters to the Editor
  2. Missing agreement between the two IMMULITE® PSA assays
  3. “Cerebrovascular stressing”: dipyridamole-induced S100B elevation predicts ischemic cerebrovascular events
  4. Discrepancy in lamellar body counts (LBCs) between the Sysmex XE-2100 and Sysmex XT-2000i instruments
  5. Interphase fluorescent in situ hybridization detection of the 7q11.23 chromosomal inversion in a clinical laboratory: automated versus manual scoring
  6. Adrenocorticotropic hormone stability in preanalytical phase depends on temperature and proteolytic enzyme inhibitor
  7. The impact on costs and efficiency of reducing the number of collected tubes
  8. Improved software on the Sysmex XE-5000 BF mode for counting leukocytes in cerebrospinal fluid
  9. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 are significantly related to PAPP-A levels
  10. Preliminary evaluation of complete blood cell count on Mindray BC-6800
  11. Rational use of laboratory tests: albuminuria
  12. Masthead
  13. Masthead
  14. Editorials
  15. Fifty years of CCLM – invitation to join us for a reception in Milan
  16. Personalized (laboratory) medicine: a bridge to the future
  17. PSA, PCA3 and the phi losophy of prostate cancer management
  18. Reviews
  19. Gender medicine: a task for the third millennium
  20. Evaluation of [−2] proPSA and Prostate Health Index (phi) for the detection of prostate cancer: a systematic review and meta-analysis
  21. Harmonization in laboratory medicine: the complete picture
  22. Opinion Papers
  23. Glycemic control in the clinical management of diabetic patients
  24. Time for a conceptual shift in assessment of internal quality control for whole blood or cell-based testing systems? An evaluation using platelet function and the PFA-100 as a case example
  25. Guidelines and Recommendations
  26. A position paper of the EFLM Committee on Education and Training and Working Group on Distance Education Programmes/E-Learning: developing an e-learning platform for the education of stakeholders in laboratory medicine
  27. General Clinical Chemistry and Laboratory Medicine
  28. A novel weighted cumulative delta-check method for highly sensitive detection of specimen mix-up in the clinical laboratory
  29. Identification and quantification of hemoglobins in whole blood: the analytical and organizational aspects of Capillarys 2 Flex Piercing compared with agarose electrophoresis and HPLC methods
  30. Determination of the fatty acid profile of neutral lipids, free fatty acids and phospholipids in human plasma
  31. Urinary iodine concentrations of pregnant women in Ukraine
  32. Delay in the measurement of eosin-5′-maleimide (EMA) binding does not affect the test result for the diagnosis of hereditary spherocytosis
  33. Faecal calprotectin: comparative study of the Quantum Blue rapid test and an established ELISA method
  34. Target analyte quantification by isotope dilution LC-MS/MS directly referring to internal standard concentrations – validation for serum cortisol measurement
  35. Reference Values and Biological Variations
  36. Reference values and upper reference limits for 26 trace elements in the urine of adults living in Belgium
  37. Biological variation and reference change values of common clinical chemistry and haematologic laboratory analytes in the elderly population
  38. Indirect determination of pediatric blood count reference intervals
  39. Cancer Diagnostics
  40. Suitability of quality control materials for prostate-specific antigen (PSA) measurement: inter-method variability of common tumor marker control materials
  41. Prostate cancer antigen 3 (PCA3) RNA detection in blood and tissue samples for prostate cancer diagnosis
  42. Serum levels of cancer biomarkers in diabetic and non-diabetic proteinuric patients: a preliminary study
  43. Infectious Diseases
  44. Polymorphic mononuclear neutrophils CD64 index for diagnosis of sepsis in postoperative surgical patients and critically ill patients
  45. Plasma long pentraxin 3 (PTX3) concentration is a novel marker of disease activity in patients with community-acquired pneumonia
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 28.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/cclm-2012-0279/html?lang=en
Scroll to top button