Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Severe acute graft-versus-host disease increases the incidence of blood stream infection and mortality after allogeneic hematopoietic cell transplantation: Japanese transplant registry study

Bone Marrow Transplantation volume 56, pages 2125–2136 (2021)Cite this article

Subjects

Abstract

This study aimed to clarify the risk factors and prognosis associated with blood stream infection (BSI) in allogeneic hematopoietic cell transplantation (allo-HCT), and the relationship between BSI and acute graft-versus-host disease (aGVHD). This retrospective analysis included 11,098 patients in the Japanese national transplant registry. A total of 2172 patients developed BSI after allo-HCT, with 2332 identified pathogens. The cumulative incidences of BSI were 15.5% at 30 days and 20.9% at 100 days after allo-HCT. In a multivariate analysis, severe (grade III–IV) aGVHD was associated with a higher risk of BSI (vs. grade 0–I aGVHD: hazard ratio [HR] 3.34 [95% confidence interval (CI), 2.85–3.92; P < 0.001]). In a multivariate analysis, severe aGVHD before BSI was associated with a higher risk of overall mortality after BSI (vs. grade 0–I aGVHD: HR 2.61 [95% CI 2.18–3.11; P < 0.001]). In addition, BSI (vs. no-BSI: HR 1.20 [95% CI, 1.12–1.29; P < 0.001]) and severe aGVHD (vs. grade 0–I aGVHD: HR 1.97 [95% CI, 1.83–2.12; P < 0.001]) were independent risk factors for overall mortality after allo-HCT. In the setting of allo-HCT, severe aGVHD was associated with increases in both BSI incidence and post-BSI overall mortality. Furthermore, BSI was an independent risk factor for overall mortality.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The cumulative incidence of BSI.
Fig. 2: The cumulative incidence of BSI grouped according to aGVHD grade (semi-landmark plots).
Fig. 3: The probability of overall survival after BSI.
Fig. 4: The probability of overall survival (semi-landmark plots).

Similar content being viewed by others

References

  1. Collin BA, Leather HL, Wingard JR, Ramphal R. Evolution, incidence, and susceptibility of bacterial bloodstream isolates from 519 bone marrow transplant patients. Clin Infect Dis. 2001;33:947–53. https://doi.org/10.1086/322604.

    Article  CAS  PubMed  Google Scholar 

  2. Ortega M, Rovira M, Almela M, Marco F, de la Bellacasa JP, Martinez JA, et al. Bacterial and fungal bloodstream isolates from 796 hematopoietic stem cell transplant recipients between 1991 and 2000. Ann Hematol. 2005;84:40–6. https://doi.org/10.1007/s00277-004-0909-0.

    Article  PubMed  Google Scholar 

  3. Poutsiaka DD, Price LL, Ucuzian A, Chan GW, Miller KB, Snydman DR. Blood stream infection after hematopoietic stem cell transplantation is associated with increased mortality. Bone Marrow Transplant. 2007;40:63–70. https://doi.org/10.1038/sj.bmt.1705690.

    Article  CAS  PubMed  Google Scholar 

  4. Mikulska M, Del Bono V, Raiola AM, Bruno B, Gualandi F, Occhini D, et al. Blood stream infections in allogeneic hematopoietic stem cell transplant recipients: reemergence of Gram-negative rods and increasing antibiotic resistance. Biol Blood Marrow Transplant. 2009;15:47–53. https://doi.org/10.1016/j.bbmt.2008.10.024.

    Article  CAS  PubMed  Google Scholar 

  5. Busca A, Cavecchia I, Locatelli F, D’Ardia S, De Rosa FG, Marmont F, et al. Blood stream infections after allogeneic stem cell transplantation: a single-center experience with the use of levofloxacin prophylaxis. Transpl Infect Dis. 2012;14:40–8. https://doi.org/10.1111/j.1399-3062.2011.00650.x.

    Article  CAS  PubMed  Google Scholar 

  6. Mikulska M, Del Bono V, Bruzzi P, Raiola AM, Gualandi F, Van Lint MT, et al. Mortality after bloodstream infections in allogeneic haematopoietic stem cell transplant (HSCT) recipients. Infection. 2012;40:271–8. https://doi.org/10.1007/s15010-011-0229-y.

    Article  CAS  PubMed  Google Scholar 

  7. Blennow O, Ljungman P, Sparrelid E, Mattsson J, Remberger M. Incidence, risk factors, and outcome of bloodstream infections during the pre-engraftment phase in 521 allogeneic hematopoietic stem cell transplantations. Transpl Infect Dis. 2014;16:106–14. https://doi.org/10.1111/tid.12175.

    Article  CAS  PubMed  Google Scholar 

  8. Young JH, Logan BR, Wu J, Wingard JR, Weisdorf DJ, Mudrick C, et al. Infections after transplantation of bone marrow or peripheral blood stem cells from unrelated donors. Biol Blood Marrow Transplant. 2016;22:359–70. https://doi.org/10.1016/j.bbmt.2015.09.013.

    Article  PubMed  Google Scholar 

  9. Weisser M, Theilacker C, Tschudin Sutter S, Babikir R, Bertz H, Gotting T, et al. Secular trends of bloodstream infections during neutropenia in 15 181 haematopoietic stem cell transplants: 13-year results from a European multicentre surveillance study (ONKO-KISS). Clin Microbiol Infect. 2017;23:854–9. https://doi.org/10.1016/j.cmi.2017.03.020.

    Article  CAS  PubMed  Google Scholar 

  10. Gudiol C, Garcia-Vidal C, Arnan M, Sanchez-Ortega I, Patino B, Duarte R, et al. Etiology, clinical features and outcomes of pre-engraftment and post-engraftment bloodstream infection in hematopoietic SCT recipients. Bone Marrow Transplant. 2014;49:824–30. https://doi.org/10.1038/bmt.2014.37.

    Article  CAS  PubMed  Google Scholar 

  11. Ustun C, Kim S, Chen M, Beitinjaneh AM, Brown VI, Dahi PB, et al. Increased overall and bacterial infections following myeloablative allogeneic HCT for patients with AML in CR1. Blood Adv. 2019;3:2525–36. https://doi.org/10.1182/bloodadvances.2019000226.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ustun C, Young JH, 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 Transplant. 2019;54:1254–65. https://doi.org/10.1038/s41409-018-0401-4.

    Article  PubMed  Google Scholar 

  13. Shallis RM, Terry CM, Lim SH. Changes in intestinal microbiota and their effects on allogeneic stem cell transplantation. Am J Hematol. 2018;93:122–8. https://doi.org/10.1002/ajh.24896.

    Article  PubMed  Google Scholar 

  14. Shono Y, van den Brink MRM. Gut microbiota injury in allogeneic haematopoietic stem cell transplantation. Nat Rev Cancer. 2018;18:283–95. https://doi.org/10.1038/nrc.2018.10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fuji S, Kapp M, Einsele H. Possible implication of bacterial infection in acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Front Oncol. 2014;4:89. https://doi.org/10.3389/fonc.2014.00089.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Poutsiaka DD, Munson D, Price LL, Chan GW, Snydman DR. Blood stream infection (BSI) and acute GVHD after hematopoietic SCT (HSCT) are associated. Bone Marrow Transplant. 2011;46:300–7. https://doi.org/10.1038/bmt.2010.112.

    Article  CAS  PubMed  Google Scholar 

  17. Castagnola E, Bagnasco F, Bandettini R, Caviglia I, Morreale G, Lanino E, et al. Role of acute graft-versus-host disease in the risk of bacteremia and invasive fungal disease after allogeneic hemopoietic stem cell transplantation in children. Results from a single-center observational study. Biol Blood Marrow Transplant. 2014;20:1068–73. https://doi.org/10.1016/j.bbmt.2014.03.026.

    Article  PubMed  Google Scholar 

  18. Levinson A, Pinkney K, Jin Z, Bhatia M, Kung AL, Foca MD, et al. Acute gastrointestinal graft-vs-host disease is associated with increased enteric bacterial bloodstream infection density in pediatric allogeneic hematopoietic cell transplant recipients. Clin Infect Dis. 2015;61:350–7. https://doi.org/10.1093/cid/civ285.

    Article  CAS  PubMed  Google Scholar 

  19. Satwani P, Freedman JL, Chaudhury S, Jin Z, Levinson A, Foca MD, et al. A multicenter study of bacterial blood stream infections in pediatric allogeneic hematopoietic cell transplantation recipients: the role of acute gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant. 2017;23:642–7. https://doi.org/10.1016/j.bbmt.2017.01.073.

    Article  PubMed  Google Scholar 

  20. Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A, et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol. 2007;86:269–74. https://doi.org/10.1532/ijh97.06239.

    Article  PubMed  Google Scholar 

  21. Atsuta Y. Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data). Int J Hematol. 2016;103:3–10. https://doi.org/10.1007/s12185-015-1894-x.

  22. Kanda J. Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation. Int J Hematol. 2016;103:11–9. https://doi.org/10.1007/s12185-015-1907-9.

    Article  CAS  PubMed  Google Scholar 

  23. 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 Transplant. 2009;15:1628–33. https://doi.org/10.1016/j.bbmt.2009.07.004.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant. 2009;15:367–9. https://doi.org/10.1016/j.bbmt.2008.12.497.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–8.

    CAS  PubMed  Google Scholar 

  26. Kanda J, Hishizawa M, Utsunomiya A, Taniguchi S, Eto T, Moriuchi Y, et al. Impact of graft-versus-host disease on outcomes after allogeneic hematopoietic cell transplantation for adult T-cell leukemia: a retrospective cohort study. Blood. 2012;119:2141–8. https://doi.org/10.1182/blood-2011-07-368233.

    Article  CAS  PubMed  Google Scholar 

  27. Kim S, Logan B, Riches M, Chen M, Ahn KW. Statistical methods for time-dependent variables in hematopoietic cell transplantation studies. Biol Blood Marrow Transplant. 2020. https://doi.org/10.1016/j.bbmt.2020.09.034.

  28. Cortese G, Andersen PK. Competing risks and time-dependent covariates. Biom J. 2010;52:138–58. https://doi.org/10.1002/bimj.200900076.

    Article  PubMed  Google Scholar 

  29. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8. https://doi.org/10.1038/bmt.2012.244.

    Article  CAS  Google Scholar 

  30. Mielcarek M, Storer BE, Boeckh M, Carpenter PA, McDonald GB, Deeg HJ, et al. Initial therapy of acute graft-versus-host disease with low-dose prednisone does not compromise patient outcomes. Blood. 2009;113:2888–94. https://doi.org/10.1182/blood-2008-07-168401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dignan FL, Clark A, Amrolia P, Cornish J, Jackson G, Mahendra P, et al. Diagnosis and management of acute graft-versus-host disease. Br J Haematol. 2012;158:30–45. https://doi.org/10.1111/j.1365-2141.2012.09129.x.

    Article  CAS  PubMed  Google Scholar 

  32. MacMillan ML, Weisdorf DJ, Wagner JE, DeFor TE, Burns LJ, Ramsay NK, et al. Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems. Biol Blood Marrow Transplant. 2002;8:387–94.

    Article  CAS  Google Scholar 

  33. Deeg HJ. How I treat refractory acute GVHD. Blood. 2007;109:4119–26. https://doi.org/10.1182/blood-2006-12-041889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Matsumura-Kimoto Y, Inamoto Y, Tajima K, Kawajiri A, Tanaka T, Hirakawa T, et al. Association of cumulative steroid dose with risk of infection after treatment for severe acute graft-versus-host disease. Biol Blood Marrow Transplant. 2016;22:1102–7. https://doi.org/10.1016/j.bbmt.2016.02.020.

    Article  CAS  PubMed  Google Scholar 

  35. Fuji S, Loffler J, Savani BN, Einsele H, Kapp M. Hyperglycemia as a possible risk factor for mold infections-the potential preventative role of intensified glucose control in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2017;52:657–62. https://doi.org/10.1038/bmt.2016.306.

    Article  CAS  PubMed  Google Scholar 

  36. Averbuch D, Tridello G, Hoek J, Mikulska M, Akan H, Yanez San Segundo L, et al. Antimicrobial resistance in gram-negative rods causing bacteremia in hematopoietic stem cell transplant recipients: intercontinental prospective study of the infectious diseases working party of the European Bone Marrow Transplantation Group. Clin Infect Dis. 2017;65:1819–28. https://doi.org/10.1093/cid/cix646.

    Article  CAS  PubMed  Google Scholar 

  37. Mikulska M, Del Bono V, Prinapori R, Boni L, Raiola AM, Gualandi F, et al. Risk factors for enterococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2010;12:505–12. https://doi.org/10.1111/j.1399-3062.2010.00544.x.

    Article  CAS  PubMed  Google Scholar 

  38. Vydra J, Shanley RM, George I, Ustun C, Smith AR, Weisdorf DJ, et al. Enterococcal bacteremia is associated with increased risk of mortality in recipients of allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012;55:764–70. https://doi.org/10.1093/cid/cis550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Papanicolaou GA, Ustun C, Young JH, Chen M, Kim S, Woo Ahn K, et al. Bloodstream infection due to vancomycin-resistant enterococcus is associated with increased mortality after hematopoietic cell transplantation for acute leukemia and myelodysplastic syndrome: a multicenter, retrospective cohort study. Clin Infect Dis. 2019;69:1771–9. https://doi.org/10.1093/cid/ciz031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Junghanss C, Marr KA, Carter RA, Sandmaier BM, Maris MB, Maloney DG, et al. Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant. 2002;8:512–20.

    Article  Google Scholar 

  41. Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med. 2004;351:2276–85. https://doi.org/10.1056/NEJMoa041469.

    Article  CAS  PubMed  Google Scholar 

  42. Atsuta Y, Suzuki R, Nagamura-Inoue T, Taniguchi S, Takahashi S, Kai S, et al. Disease-specific analyses of unrelated cord blood transplantation compared with unrelated bone marrow transplantation in adult patients with acute leukemia. Blood. 2009;113:1631–8. https://doi.org/10.1182/blood-2008-03-147041.

    Article  PubMed  Google Scholar 

  43. Murata M, Nakasone H, Kanda J, Nakane T, Furukawa T, Fukuda T, et al. Clinical factors predicting the response of acute graft-versus-host disease to corticosteroid therapy: an analysis from the GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2013;19:1183–9. https://doi.org/10.1016/j.bbmt.2013.05.003.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to the Transplant Complications Working Group of the Japan Society for Hematopoietic Cell Transplantation and the JDCHCT for helping with this study.

Transplant Complications Working Group of The Japan Society for Hematopoietic Cell Transplantation

Yoshitaka Inoue1,2, Keiji Okinaka2, Shigeo Fuji3, Masao Ogata13, Takahiro Fukuda2

Funding

This research was partially supported by the National Cancer Center Research and Development Fund (29-A-14).

Author information

Authors and Affiliations

  1. Department of Hematology, Kumamoto University Hospital, Kumamoto, Japan

    Yoshitaka Inoue

  2. Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan

    Yoshitaka Inoue, Keiji Okinaka, Yoshihiro Inamoto & Takahiro Fukuda

  3. Department of Hematology, Osaka International Cancer Institute, Osaka, Japan

    Shigeo Fuji

  4. Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital, Tokyo, Japan

    Naoyuki Uchida

  5. Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

    Takashi Toya

  6. Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan

    Kazuhiro Ikegame

  7. Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan

    Tetsuya Eto

  8. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Yukiyasu Ozawa

  9. Department of Hematology, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima, Japan

    Koji Iwato

  10. Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan

    Yoshinobu Kanda

  11. Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan

    Yoshiko Atsuta

  12. Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yoshiko Atsuta

  13. Department of Hematology, Oita University Hospital, Oita, Japan

    Masao Ogata

Authors
  1. Yoshitaka Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keiji Okinaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shigeo Fuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshihiro Inamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naoyuki Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takashi Toya
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazuhiro Ikegame
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tetsuya Eto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yukiyasu Ozawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Koji Iwato
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yoshinobu Kanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yoshiko Atsuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Masao Ogata
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Takahiro Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Transplant Complications Working Group of The Japan Society for Hematopoietic Cell Transplantation

  • Yoshitaka Inoue
  • , Keiji Okinaka
  • , Shigeo Fuji
  • , Masao Ogata
  •  & Takahiro Fukuda

Contributions

YI, KO, SF, YI, and TF participated in research design, data analysis, and writing of the paper. NU, TT, KI, TE, YO, KI, YK, YA, and MO participated in writing of the paper.

Corresponding author

Correspondence to Yoshitaka Inoue.

Ethics declarations

Conflict of interest

YA reports Honoraria (e.g., lecture fees) from Chugai Pharmaceutical Co. Ltd, Kyowa Kirin Co., Ltd, Bristol-Myers Squibb Co., Ltd, Yakult Honsha Co., Ltd., Janssen Pharmaceutical K.K., and Otsuka Pharmaceutical Co., Ltd, outside the submitted work. The other authors declare no competing interests associated with this paper.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Members of the Transplant Complications Working Group of The Japan Society for Hematopoietic Cell Transplantation are listed below Acknowledgements.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Inoue, Y., Okinaka, K., Fuji, S. et al. Severe acute graft-versus-host disease increases the incidence of blood stream infection and mortality after allogeneic hematopoietic cell transplantation: Japanese transplant registry study. Bone Marrow Transplant 56, 2125–2136 (2021). https://doi.org/10.1038/s41409-021-01291-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-021-01291-0

This article is cited by

Search

Advanced search

Quick links