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Grading bloodstream infection risk using citrulline as a biomarker of intestinal mucositis in patients receiving intensive therapy

Abstract

Earlier studies have suggested that severe intestinal mucositis (IM; citrulline < 10 µmol/L) is an independent risk factor for bloodstream infections (BSI) after cytotoxic therapy. Our aim was to grade IM in patients receiving commonly used chemotherapy and conditioning regimens, and characterize its relationship with BSI incidence. In a retrospective analysis of remission induction (RI) chemotherapy, or conditioning for autologous and allogeneic hematopoietic stem cell transplantation (HSCT; myeloablative conditioning [MAC] and non-myeloablative and reduced-intensity conditioning [NMA/RIC]), data were collected on central venous catheter (CVC) characteristics and BSI. The relationship between BSI occurrence and the degree of IM (determined by citrulline levels) and neutropenia was analyzed. In 626 CVC episodes, 268 (42.8%) laboratory-confirmed BSIs (LCBIs) occurred, classified as mucosal barrier injury (MBI)-LCBIs in 179 (28.6%) episodes, central line–associated BSIs in 113 (18.1%) episodes, and catheter-related BSIs in 55 (8.8%) episodes. In NMA/RIC, the mean duration of hypocitrullinemia was 0.77 days, with LCBI and MBI-LCBI occurring in 11.1% and 4.8% of episodes. In autologous HSCT, RI, and MAC allogeneic HSCT, LCBI and MBI-LCBI occurred frequently (40.0–63.8% and 22.8–53.2% of episodes, respectively) and the mean duration of hypocitrullinemia was significantly higher (9.2–13.8 days). There was a strong correlation between LCBI and the duration of hypocitrullinemia (Pearson’s correlation coefficient R = 0.96), as opposed to the relationship between LCBI and the duration of neutropenia (R = 0.42). We conclude that citrulline can be used to grade BSI risk for commonly used intensive treatment regimens.

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Fig. 1: Citrulline concentrations over time after the start of chemotherapy.
Fig. 2: Summary of the citrulline concentrations over time for all treatment regimens.
Fig. 3: Time to occurrence of bacteremia.
Fig. 4: Correlation between LCBI, citrulline, and neutropenia.

References

  1. Dandoy CE, Ardura MI, Papanicolaou GA, Auletta JJ. Bacterial bloodstream infections in the allogeneic hematopoietic cell transplant patient: new considerations for a persistent nemesis. Bone Marrow Transpl. 2017;52:1091–106.

    Article  CAS  Google Scholar 

  2. Richters A, van Vliet M, Peer PG, Verweij PE, Laros-van Gorkom BAP, Blijlevens NMA. et al. Incidence of and risk factors for persistent gram-positive bacteraemia and catheter-related thrombosis in haematopoietic stem cell transplantation. Bone Marrow Transpl. 2014;49:264–9.

    Article  CAS  Google Scholar 

  3. Ustun C, Young J-AH, Papanicolaou GA, Kim S, Ahn KW, Chen M, et al. Bacterial blood stream infections (BSIs), particularly post-engraftment BSIs, are associated with increased mortality after allogeneic hematopoietic cell transplantation. Bone Marrow Transpl. 2019;54:1254–65.

    Article  Google Scholar 

  4. Dandoy CE, Haslam D, Lane A, Jodele S, Demmel K, El-Bietar J, et al. Healthcare burden, risk factors, and outcomes of mucosal barrier injury laboratory-confirmed bloodstream infections after stem cell transplantation. Biol Blood Marrow Transpl. 2016;22:1671–7.

    Article  Google Scholar 

  5. Verlinden A, Mikulska M, Knelange NS, Averbuch D, Styczynski J. Current antimicrobial practice in febrile neutropenia across Europe and Asia: the EBMT Infectious Disease Working Party survey. Bone Marrow Transpl. 2020;55:1588–94.

    Article  Google Scholar 

  6. Kelly MS, Ward DV, Severyn CJ, Arshad M, Heston SM, Jenkins K, et al. Gut colonization preceding mucosal barrier injury bloodstream infection in pediatric hematopoietic stem cell transplantation recipients. Biol Blood Marrow Transpl. 2019;25:2274–80.

    Article  CAS  Google Scholar 

  7. Rashidi A, Kaiser T, Graiziger C, Holtan SG, Rehman TU, Weisdorf DJ, et al. Specific gut microbiota changes heralding bloodstream infection and neutropenic fever during intensive chemotherapy. Leukemia. 2020;34:312–6.

    Article  Google Scholar 

  8. Holler E, Butzhammer P, Schmid K, Hundsrucker C, Koestler J, Peter K, et al. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transpl. 2014;20:640–5.

    Article  Google Scholar 

  9. Peled JU, Gomes ALC, Devlin SM, Littmann ER, Taur Y, Sung AD, et al. Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation. N. Engl J Med. 2020;382:822–34.

    Article  CAS  Google Scholar 

  10. van Vliet MJ, Harmsen HJ, de Bont ES, Tissing WJ. The role of intestinal microbiota in the development and severity of chemotherapy-induced mucositis. PLoS Pathog. 2010;6:e1000879.

    Article  Google Scholar 

  11. van Vliet MJ, Tissing WJ, Dun CA, Meessen NE, Kamps WA, de Bont ES, et al. Chemotherapy treatment in pediatric patients with acute myeloid leukemia receiving antimicrobial prophylaxis leads to a relative increase of colonization with potentially pathogenic bacteria in the gut. Clin Infect Dis. 2009;49:262–70.

    Article  Google Scholar 

  12. Jenq RR, Ubeda C, Taur Y, Menezes CC, Khanin R, Dudakov JA, et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med. 2012;209:903–11.

    Article  CAS  Google Scholar 

  13. Shono Y, Docampo MD, Peled JU, Perobelli SM, Velardi E, Tsai JJ, et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med. 2016;8:339ra371.

  14. Shono Y, van den Brink MRM. Gut microbiota injury in allogeneic haematopoietic stem cell transplantation. Nat Rev Cancer. 2018;18:283–95.

    Article  CAS  Google Scholar 

  15. Taur Y, Jenq RR, Perales MA, Littmann ER, Morjaria S, Ling L, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014;124:1174–82.

    Article  CAS  Google Scholar 

  16. Taur Y, Xavier JB, Lipuma L, Ubeda C, Goldberg J, Gobourne A, et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012;55:905–14.

    Article  CAS  Google Scholar 

  17. Rashidi A, Kaiser T, Graiziger C, Holtan SG, Rehman TU, Weisdorf DJ, et al. Gut dysbiosis during antileukemia chemotherapy versus allogeneic hematopoietic cell transplantation. Cancer. 2020;126:1434–47.

    Article  CAS  Google Scholar 

  18. Centers for Disease Control and Prevention. Bloodstream Infection Event (Central line-associated bloodstream infection and non-central line-associated bloodstream infection), 2020. https://www.cdc.gov/nhsn/pdfs/pscmanual/4psc_clabscurrent.pdf.

  19. Metzger KE, Rucker Y, Callaghan M, Churchill M, Jovanovic BD, Zembower TR, et al. The burden of mucosal barrier injury laboratory-confirmed bloodstream infection among hematology, oncology, and stem cell transplant patients. Infect Control Hosp Epidemiol. 2015;36:119–24.

    Article  Google Scholar 

  20. See I, Soe MM, Epstein L, Edwards JR, Magill SS, Thompson ND. Impact of removing mucosal barrier injury laboratory-confirmed bloodstream infections from central line-associated bloodstream infection rates in the National Healthcare Safety Network, 2014. Am J Infect Control. 2017;45:321–3.

    Article  Google Scholar 

  21. Harris AC, Young R, Devine S, Hogan WJ, Ayuk F, Bunworasate U, et al. International, multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the mount sinai acute GVHD International Consortium. Biol Blood Marrow Transpl. 2016;22:4–10.

    Article  Google Scholar 

  22. Spyridonidis A, Labopin M, Savani BN, Niittyvuopio R, Blaise D, Craddock C, et al. Redefining and measuring transplant conditioning intensity in current era: a study in acute myeloid leukemia patients. Bone Marrow Transpl. 2020;55:1114–25.

    Article  CAS  Google Scholar 

  23. Herbers AH, Blijlevens NM, Donnelly JP, de Witte TJ. Bacteraemia coincides with low citrulline concentrations after high-dose melphalan in autologous HSCT recipients. Bone Marrow Transpl. 2008;42:345–9.

    Article  CAS  Google Scholar 

  24. Herbers AH, de Haan AF, van der Velden WJ, Donnelly JP, Blijlevens NM. Mucositis not neutropenia determines bacteremia among hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2014;16:279–85.

    Article  CAS  Google Scholar 

  25. Hueso T, Ekpe K, Mayeur C, Gatse A, Joncquel-Chevallier Curt M, Gricourt G, et al. Impact and consequences of intensive chemotherapy on intestinal barrier and microbiota in acute myeloid leukemia: the role of mucosal strengthening. Gut Microbes. 2020;12:1800897.

    Article  Google Scholar 

  26. van der Kooi TI, Wille JC, van Benthem BH. Catheter application, insertion vein and length of ICU stay prior to insertion affect the risk of catheter-related bloodstream infection. J Hosp Infect. 2012;80:238–44.

    Article  Google Scholar 

  27. Dutch National Institute for Public Health and the Environment (RIVM). Definitions CRBSI, 2017 (Dutch: Definities lijnsepsis. https://www.rivm.nl/prezies/incidentieonderzoek-lijnsepsis/protocol-module-lijnsepsis/protocollen-lijnsepsis-archief.

  28. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transpl. 2009;15:1628–33.

    Article  Google Scholar 

  29. O’Grady NP, Alexander M, Burns LA, Dellinger EP, Garland J, Heard SO, et al. Guidelines for the prevention of intravascular catheter-related infections. Am J Infect Control. 2011;39:S1–34.

    Article  Google Scholar 

  30. Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O’Grady NP, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49:1–45.

    Article  CAS  Google Scholar 

  31. van der Velden WJ, Herbers AH, Feuth T, Schaap NP, Donnelly JP, Blijlevens NM. Intestinal damage determines the inflammatory response and early complications in patients receiving conditioning for a stem cell transplantation. PLoS ONE. 2010;5:e15156.

    Article  Google Scholar 

  32. van der Velden WJ, Blijlevens NM, Feuth T, Donnelly JP. Febrile mucositis in haematopoietic SCT recipients. Bone Marrow Transpl. 2009;43:55–60.

    Article  Google Scholar 

  33. 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;124:1210–9.

    Article  CAS  Google Scholar 

  34. De Pietri S, Frandsen TL, Christensen M, Grell K, Rathe M, Muller K. Citrulline as a biomarker of bacteraemia during induction treatment for childhood acute lymphoblastic leukaemia. Pediatr Blood Cancer. 2021;68:e28793.

  35. L’Heriteau F, Olivier M, Maugat S, Joly C, Merrer J, Thaler F, et al. Impact of a five-year surveillance of central venous catheter infections in the REACAT intensive care unit network in France. J Hosp Infect. 2007;66:123–9.

    Article  Google Scholar 

  36. Khan N, Lindner S, Gomes ALC, Devlin SM, Shah SL, Sung AD, et al. Fecal microbiota diversity disruption and clinical outcomes after auto-HCT: a multicenter observational study. Blood. 2021;137:1527–37.

    Article  CAS  Google Scholar 

  37. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:427–31.

    Article  Google Scholar 

  38. Cruciani M, Malena M, Bosco O, Nardi S, Serpelloni G, Mengoli C. Reappraisal with meta-analysis of the addition of Gram-positive prophylaxis to fluoroquinolone in neutropenic patients. J Clin Oncol. 2003;21:4127–37.

    Article  CAS  Google Scholar 

  39. Avery RK. Adding Gram-positive prophylaxis to fluoroquinolone regimens reduces streptococcal bacteraemias, but prophylaxis remains controversial. Cancer Treat Rev. 2004;30:385–8.

    Article  Google Scholar 

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CEMM, WJFMV and NMAB designed the study. SF maintained the CVC registry. CEMM, AFJH, LFJG and WJFMV analyzed and interpreted the data. AFJH and CEMM performed the statistical analysis. CEMM, WJFMV and NMAB wrote the manuscript. All authors critically revised and approved the final manuscript.

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Correspondence to C. E. M. de Mooij.

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de Mooij, C.E.M., van der Velden, W.J.F.M., de Haan, A.F.J. et al. Grading bloodstream infection risk using citrulline as a biomarker of intestinal mucositis in patients receiving intensive therapy. Bone Marrow Transplant 57, 1373–1381 (2022). https://doi.org/10.1038/s41409-022-01719-1

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