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Post-Transplant Events

Bacteraemia coincides with low citrulline concentrations after high-dose melphalan in autologous HSCT recipients

Bone Marrow Transplantation volume 42, pages 345–349 (2008)Cite this article

Abstract

Mucosal damage to the intestines induced by myeloablative conditioning for allogeneic PBSC transplant (PBSCT) can be determined by the concentration of citrulline, which is a functional marker of small intestinal enterocytes. Low citrulline concentrations in blood coincide with and are a response to severe mucosal barrier injury. We treated 29 patients with high-dose melphalan 200 mg/m2 (Mel-200) to prepare for an autologous PBSCT and collected plasma samples from each patient starting before the myeloablative regimen and three times per week thereafter until discharge. The baseline citrulline concentration was 27.6 mM±4.0 (mean±95% confidence interval; CI), and citrulline concentrations declined rapidly thereafter reaching a nadir averaging 6.7 mM±2.7, 12 days after starting Mel-200. Citrulline concentrations, only increased gradually and were still low (12 mM±4) at discharge. A total of 20 patients developed fever, which was associated with bacteraemia in 10 cases. Their mean citrulline concentrations were lower at 5.5 mM±1.5 than were those of patients without bacteraemia (10.2 mM±3.9). Importantly, neither the number of preceding neutropenic days nor the mean C-reactive protein (CRP) concentration at the onset of fever was different between these two groups. In conclusion, citrulline concentrations rapidly decline after Mel-200 reflecting intestinal mucosal barrier injury. Low citrulline, rather than the duration of neutropenia, is associated with bacteraemia indicating the importance of an intact mucosal barrier in neutropenic patients.

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References

  1. Blijlevens NMA, Lutgens LCHW, Schattenberg AVMB, De Pauw BE . Citrulline: a potentially simple quantitative marker of intestinal epithelial damage following myeloablative therapy. Bone Marrow Transplant 2004; 34: 193–196.

    Article  CAS  PubMed  Google Scholar 

  2. Ellis M . Preventing microbial translocation in haematological malignancy. Br J Haematol 2004; 125: 282–293.

    Article  PubMed  Google Scholar 

  3. Crenn P, Vahedi K, Lavergne-Slove A, Cynober L, Matuchansky C, Messing B . Plasma citrulline: a marker of enterocyte mass in villous atrophy-associated small bowel disease. Gastroenterology 2003; 124: 1210–1219.

    Article  CAS  PubMed  Google Scholar 

  4. Blijlevens NMA, Donnelly JP, De Pauw BE . Inflammatory response to mucosal barrier injury after myeloablative therapy in allogeneic stem cell transplant recipients. Bone Marrow Transplant 2005; 36: 703–707.

    Article  CAS  PubMed  Google Scholar 

  5. Ruescher TJ, Sodeifi A, Scrivani SJ, Kaban LB, Sonis ST . The impact of mucositis on alpha-hemolytic streptococcal infection in patients undergoing autologous bone marrow transplantation for hematologic malignancies. Cancer 1998; 82: 2275–2281.

    Article  CAS  PubMed  Google Scholar 

  6. Jones BN, Giligan JP . o-Phthaldialdehyde precolumn derivatization and reversed-phase high-performance liquid chromatography of polypeptide hydrolysates and physiological fluids. J Chromatogr 1983; 266: 471–482.

    Article  CAS  PubMed  Google Scholar 

  7. Donnelly JP, Muus P, Schattenberg A, De Witte T, Horrevorts A, De Pauw BE . A scheme for daily monitoring of oral mucositis in allogenic BMT recipients. Bone Marrow Transplant 1992; 9: 409–413.

    CAS  PubMed  Google Scholar 

  8. Wardley AM, Jayson GC, Swindell R, Morgenstern GR, Chang J, Bloor R et al. Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haematopoietic progenitor rescue. Br J Haematol 2000; 110: 292–299.

    Article  CAS  PubMed  Google Scholar 

  9. Cockcroft DW, Gault MH . Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41.

    Article  CAS  PubMed  Google Scholar 

  10. Bodey GP, Buckley M, Sathe YS, Freireich EJ . Quantitative relationships between circulating leucocytes and infections in patients with acute leukemia. Ann Intern Med 1966; 64: 328–340.

    Article  CAS  PubMed  Google Scholar 

  11. Bow EJ . Management of the febrile neutropenic cancer patient: lessons from 40 years of study. Clin Microbiol Infect 2005; 11: 24–29.

    Article  PubMed  Google Scholar 

  12. Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg J et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem cell transplantation. J Clin Oncol 2001; 19: 2201–2205.

    Article  CAS  PubMed  Google Scholar 

  13. Blijlevens N, Schwenkglenks M, Bacon P, DÁddio A, Einsele H, Maertens J et al. Prospective oral mucositis audit: oral mucositis in patients receiving high-dose melphalan or BEAM conditioning chemotherapy. European Blood and Marrow Transplantation Mucositis Advisory Group. J Clin Oncol 2008; 26: 1519–1525.

    Article  CAS  PubMed  Google Scholar 

  14. Blijlevens NMA, van ‘t Land B, Donnelly JP, M'Rabet L, De Pauw BE . Measuring mucosal damage induced by cytotoxic therapy. Support Care Cancer 2004; 12: 227–233.

    Article  CAS  PubMed  Google Scholar 

  15. Von Lilienfeld-Toal M, Dietrich MP, Glasmacher A, Lehman L, Breij P, Hahn C et al. Markers of bacteremia in febrile neutropenic patients with hematological malignancies: procalcitonin and IL-6 are more reliable than C-reactive protein. Eur J Clin Microbiol Infect Dis 2004; 23: 539–544.

    CAS  PubMed  Google Scholar 

  16. Ortega M, Ravira M, Almela M, Dela Bellacasa JP, Carreras E, Menza J . Measurement of C-reactive protein in adults with febrile neutropenia after hematopoietic cell transplantation. Bone Marrow Transplant 2004; 33: 741–744.

    Article  CAS  PubMed  Google Scholar 

  17. Tsuji E, Hiki N, Nomura S, Fukushima R, Kojima J, Ogawa T et al. Simultaneous onset of acute inflammatory response, sepsis-like symptoms and intestinal mucosal injury after cancer chemotherapy. Int J Cancer 2003; 1: 303–308.

    Article  Google Scholar 

  18. Cruciani M, Rampazzo R, Malena M, Lazzarini L, Todeschini G, Messori A et al. Prophylaxis with fluoroquinolones for bacterial infections in neutropenic patients: a meta-analysis. Clin Infect Dis 1996; 23: 795–805.

    Article  CAS  PubMed  Google Scholar 

  19. Bouza E, Sousa D, Rodriquez-Creixems M, Garcia Lechuz J, Munoz P . Is the volume of blood cultured still a significant factor in the diagnosis of bloodstream infections. J Clin Microbiol 2007; 45: 2765–2769.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bik EM, Eckburg PB, Gill SR, Nelson KE, Purdom EA, Francois F et al. Molecular analysis of the bacterial microbiota in the human stomach. Proc Natl Acad Sci USA 2006; 103: 732–737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gamis AS, Howells WB, Swarte-Wallace J, Feusner JH, Buckley JD, Woods WG . Alpha hemolytic streptococcal infection during intensive treatment for acute myeloid leukemia: a report from the Children's cancer group study CCG-2891. J Clin Oncol 2000; 18: 1845–1855.

    Article  CAS  PubMed  Google Scholar 

  22. Costa SF, Micelli MH, Annaissie EJ . Mucosa or skin as source of coagulase-negative staphylococcal bacteraemia? Lancet Inf Dis 2004; 4: 278–286.

    Article  Google Scholar 

  23. Costa SF, Barone AA, Miceli MH, Van der Heijden IM, Soares RE, Levin AS et al. Colonization and molecular epidemiology of coagulase-negative Staphylococcal bacteremia in cancer patients: A pilot study. Am J Infect Control 2006; 34: 36–40.

    Article  PubMed  Google Scholar 

  24. Elting LS, Cooksley C, Chambers M, Cantor SB, Manzullo E, Rubenstein EB . The burden of cancer therapy: clinical and economic outcomes of chemotherapy-induced mucositis. Cancer 2003; 98: 1531–1539.

    Article  PubMed  Google Scholar 

  25. Ellis M, Zwaan F, Hedstrom U, Poynton C, Kristensen J, Jumaa P et al. Recombinant human interleukin 11 and bacterial infection in patients with haematological malignant disease undergoing chemotherapy: a double-blind placebo-controlled randomised trial. Lancet 2003; 25: 275–280.

    Article  Google Scholar 

  26. Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T et al. Palifermin for oral mucositis after intensive therapy for hematologic cancer. N Engl J Med 2004; 351: 2590–2598.

    Article  CAS  PubMed  Google Scholar 

  27. Klastersky J, Paesmans M, Rubenstein EB, Boyer M, Elting L, Feld R et al. The multinational association for supportive care in cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000; 18: 3038–3051.

    Article  CAS  PubMed  Google Scholar 

  28. Oude Nijhuis CSM, Vellenga E, Daenen SMGJ, Kamps WA, de Bont ESMJ . Endothelial cells are main producers of interleukin 8 through toll-like receptor 3 and 4 signalling during bacterial infection in leukopenic cancer patients. Clin Diagn Lab Immunol 2003; 10: 558–563.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Engel A, Mack E, Kern P, Kern WV . An analysis of interleukin-8, interleukin-6 and C-reactive protein concentrations to predict fever, gram-negative bacteremia and complicated infection in neutropenic cancer patients. Infection 1998; 26: 213–221.

    Article  CAS  PubMed  Google Scholar 

  30. De Bont ES, Vellenga E, Swaanenburg JC, Fidler V, Visser-van Brummen PJ, Kamps WA . Plasma IL-8 and IL-6 levels can be used to define a group with low risk of septicaemia among cancer patients with fever and neutropenia. Br J Haematol 1999; 107: 375–380.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Haematology, University Medical Centre St Radboud Nijmegen, Nijmegen, The Netherlands

    A H E Herbers, N M A Blijlevens, J P Donnelly & T J M de Witte

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  1. A H E Herbers
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  2. N M A Blijlevens
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  3. J P Donnelly
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  4. T J M de Witte
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Correspondence to A H E Herbers.

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Herbers, A., Blijlevens, N., Donnelly, J. et al. Bacteraemia coincides with low citrulline concentrations after high-dose melphalan in autologous HSCT recipients. Bone Marrow Transplant 42, 345–349 (2008). https://doi.org/10.1038/bmt.2008.170

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