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Associations between febrile neutropenia-related parameters and the risk of acute GVHD or non-relapse mortality after allogeneic hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 54, pages 707–716 (2019)Cite this article

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Abstract

Infection and inflammation can induce acute graft-vs.-host disease (aGVHD). We hypothesized that febrile neutropenia early after allogeneic hematopoietic cell transplantation (HCT) would increase the risk of aGVHD and non-relapse mortality (NRM). We retrospectively evaluated the impact of fever, C-reactive protein (CRP) concentration and blood stream infection (BSI) early after HCT on the incidence of grade II–IV aGVHD and NRM in 227 patients. Within 7 days after HCT, 91 (40.1%) patients experienced fever for at least 2 days (early-FN group). BSI occurred in 27 (11.9%) patients and the maximum CRP concentration was 2.57 mg/dl in the median. In a multivariate analysis, early-FN (hazard ratio (HR) 1.81, P = 0.007) and older recipient age (HR 1.68, P = 0.019) were significantly associated with the incidence of grade II–IV aGVHD. High-CRP and BSI were not significant risk factors for grade II–IV aGVHD. On the other hand, high-CRP was significantly associated with the incidence of NRM (HR 2.67, P = 0.004) in a multivariate analysis. In conclusion, although fever, CRP elevation and BSI are considered to be closely related events, they had different effects on the incidence of aGVHD and NRM. The development of early-FN after HCT may predict the risk of aGVHD.

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References

  1. McDonald GB. How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver. Blood. 2016;127:1544–50.

    Article  CAS  Google Scholar 

  2. 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.

    Article  CAS  Google Scholar 

  3. Deeg HJ. How I treat refractory acute GVHD. Blood. 2007;109:4119–26.

    Article  CAS  Google Scholar 

  4. Cutler Antin JHC. Manifestations and treatment of acute graft-versus-host disease. In: Appelbaum FR, Negrin RS, Antin JHFSJ, editors. Thomas’ Hematopoietic transplantation. Oxford, UK: Wiley-Blackwell; 2016. p. 1012–9.

    Chapter  Google Scholar 

  5. Ferrara JL, Antin JH. The Pathophysiology of Graft-versus-Host Disease. In: Forman SJ, Negrin RS, Antin JH, Appelbaum FR, (eds). Thomas’ Hematopoietic cell transplantation. Oxford, UK: Wiley-Blackwell; 2016. p. 146–52.

    Chapter  Google Scholar 

  6. Holler E, Kolb HJ, Möller A, Kempeni J, Liesenfeld S, Pechumer H, et al. Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation. Blood. 1990;75:1011–6.

    CAS  PubMed  Google Scholar 

  7. Piguet PF, Grau GE, Allet B, Vassalli P. Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease. J Exp Med. 1987;166:1280–9.

    Article  CAS  Google Scholar 

  8. Teshima T, Ordemann R, Reddy P, Gagin S, Liu C, Cooke KR, et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat Med. 2002;8:575–81.

    Article  CAS  Google Scholar 

  9. Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JL. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood. 1997;90:3204–13.

    CAS  PubMed  Google Scholar 

  10. Choi SW, Kitko CL, Braun T, Paczesny S, Yanik G, Mineishi S, et al. Change in plasma tumor necrosis factor receptor 1 levels in the first week after myeloablative allogeneic transplantation correlates with severity and incidence of GVHD and survival. Blood. 2008;112:1539–42.

    Article  CAS  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. Chong DLW, Sriskandan S. Pro-inflammatory mechanisms in sepsis. Contrib Microbiol. 2011; 17:86–107.

  13. Sajadi MM, Mackowiak PA. Temperature regulation and the pathogenesis of fever. In: Bennett JE, Dolin R, Blaser MJ, editors. Mandell, Douglas, and Bennett's Principles and paractice of infectious diseases. Philadelphia, USA: Elsevier Inc; 2015. p. 708–20.

  14. Bozza FA, Salluh JI, Japiassu AM, Soares M, Assis EF, Gomes RN, et al. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care. 2007;11:R49.

    Article  Google Scholar 

  15. 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.

    Article  CAS  Google Scholar 

  16. Blennow O, Mattsson J, Remberger M. Pre-engraftment blood stream infection is a risk factor for acute GVHD grades II–IV. Bone Marrow Transplant. 2013;48:1583–4.

    Article  CAS  Google Scholar 

  17. Fuji S, Kim S-W, Fukuda T, Mori S, Yamasaki S, Morita-Hoshi Y, et al. Preengraftment serum C-reactive protein (CRP) value may predict acute graft-versus-host disease and nonrelapse mortality after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2008;14:510–7.

    Article  CAS  Google Scholar 

  18. Beelen DW, Haralambie E, Brandt H, Linzenmeier G, Müller KD, Quabeck K, et al. Evidence that sustained growth suppression of intestinal anaerobic bacteria reduces the risk of acute graft-versus-host disease after sibling marrow transplantation. Blood. 1992;80:2668–76.

    CAS  PubMed  Google Scholar 

  19. Beelen DW, Elmaagacli A, Muller KD, Hirche H, Schaefer UW. Influence of intestinal bacterial decontamination using metronidazole and ciprofloxacin or ciprofloxacin alone on the development of acute graft-versus-host disease after marrow transplantation in patients with hematologic malignancies: final results and. Blood. 1999;93:3267–75.

    CAS  PubMed  Google Scholar 

  20. 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;8:339ra71 https://doi.org/10.1126/scitranslmed.aaf2311.Increased

    Article  PubMed  PubMed Central  Google Scholar 

  21. Weber D, Jenq RR, Peled JU, Taur Y, Hiergeist A, Koestler J, et al. Microbiota disruption induced by early use of broad-spectrum antibiotics is an independent risk factor of outcome after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2017;23:845–52.

    Article  CAS  Google Scholar 

  22. Simms-Waldrip TR, Sunkersett G, Coughlin LA, Savani MR, Arana C, Kim J, et al. Antibiotic-induced depletion of anti-inflammatory clostridia is associated with the development of graft-versus-host disease in pediatric stem cell transplantation patients. Biol Blood Marrow Transplant. 2017;23:820–9.

    Article  CAS  Google Scholar 

  23. 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 Transplant. 2014;20:640–5.

    Article  Google Scholar 

  24. Routy B, Letendre C, Enot D, Chénard-Poirier M, Mehraj V, Séguin NC, et al. The influence of gut-decontamination prophylactic antibiotics on acute graft-versus-host disease and survival following allogeneic hematopoietic stem cell transplantation. Oncoimmunology. 2017;6:e1258506.

    Article  Google Scholar 

  25. Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014;123:3664–71.

    Article  CAS  Google Scholar 

  26. 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:e56–93.

    Article  Google Scholar 

  27. Willems E, Humblet-Baron S, Dengis O, Seidel L, Beguin Y, Baron F. Elevations of tumor necrosis factor receptor 1 at day 7 and acute graft-versus-host disease after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. Bone Marrow Transplant. 2010;45:1442–8.

    Article  CAS  Google Scholar 

  28. Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA, et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol. 1988;6:1562–8.

    Article  CAS  Google Scholar 

  29. Kameda K, Kimura S-I, Akahoshi Y, Nakano H, Harada N, Ugai T, et al. High incidence of AfebrIle bloodstream infection detected by surveillance blood culture in patients on corticosteroid therapy after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22:371–7.

    Article  CAS  Google Scholar 

  30. Spitzer T. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;27:893–8.

    Article  CAS  Google Scholar 

  31. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18:295–304.

    Article  CAS  Google Scholar 

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

    CAS  Google Scholar 

  33. Kameda K, Kako S, Hayakawa J, Akahoshi Y, Komiya Y, Harada N, et al. Safety of avoiding systemic corticosteroid administration for grade II acute graft-versus-host disease limited to the skin. Ann Hematol. 2018;97:169–79.

    Article  CAS  Google Scholar 

  34. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452–8.

    Article  CAS  Google Scholar 

  35. Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J. 1990;265:621–36.

    Article  CAS  Google Scholar 

  36. Prat C, Sancho JM, Domínguez J, Xicoy B, Giménez M, Ferrà C, et al. Evaluation of procalcitonin, neopterin, C-reactive protein, IL-6 and IL-8 as a diagnostic marker of infection in patients with febrile neutropenia. Leuk Lymphoma. 2008;49:1752–61.

    Article  CAS  Google Scholar 

  37. min C-K, Kim SY, Eom KS, Kim YJ, Kim HJ, Lee S, et al. Patterns of C-reactive protein release following allogeneic stem cell transplantation are correlated with leukemic relapse. Bone Marrow Transplant. 2006;37:493–8.

    Article  CAS  Google Scholar 

  38. Hambach L, Eder M, Dammann E, Schrauder A, Sykora K-W, Dieterich C, et al. Diagnostic value of procalcitonin serum levels in comparison with C-reactive protein in allogeneic stem cell transplantation. Haematologica. 2002;87:643–51.

    CAS  PubMed  Google Scholar 

  39. McNeer JL, Kletzel M, Rademaker A, Alford K, O’Day K, Schaefer C, et al. Early elevation of C-reactive protein correlates with severe infection and nonrelapse mortality in children undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2010;16:350–7.

    Article  CAS  Google Scholar 

  40. Pihusch M, Pihusch R, Fraunberger P, Pihusch V, Andreesen R, Kolb HJ, et al. Evaluation of C-reactive protein, interleukin-6, and procalcitonin levels in allogeneic hematopoietic stem cell recipients. Eur J Haematol. 2006;76:93–101.

    Article  CAS  Google Scholar 

  41. Ali AM, DiPersio JF, Schroeder MA. The role of biomarkers in the diagnosis and risk stratification of acute graft-versus-host disease: a systematic review. Biol Blood Marrow Transplant. 2016;22:1552–64.

    Article  CAS  Google Scholar 

  42. Kitko CL, Paczesny S, Yanik G, Braun T, Jones D, Whitfield J, et al. Plasma elevations of tumor necrosis factor-receptor-1 at day 7 postallogeneic transplant correlate with graft-versus-host disease severity and overall survival in pediatric patients. Biol Blood Marrow Transplant. 2008;14:759–65.

    Article  Google Scholar 

  43. Epstein FH, Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340:448–54.

    Article  CAS  Google Scholar 

  44. Blomqvist A, Engblom D. Neural mechanisms of inflammation-induced fever. Neuroscience. 2018;24:381–99.

    Article  CAS  Google Scholar 

  45. Cao C, Matsumura K, Yamagata K, Watanabe Y. Cyclooxygenase-2 is induced in brain blood vessels during fever evoked by peripheral or central administration of tumor necrosis factor. Brain Res Mol Brain Res. 1998;56:45–56.

    Article  CAS  Google Scholar 

  46. Hill GR, Teshima T, Gerbitz A, Pan L, Cooke KR, Brinson YS, et al. Differential roles of IL-1 and TNF-α on graft-versus-host disease and graft versus leukemia. J Clin Invest. 1999;104:459–67.

    Article  CAS  Google Scholar 

  47. Park M-J, Lee SH, Lee S-H, Lee E-J, Kim E-K, Choi JY, et al. IL-1 receptor blockade alleviates graft-versus-host disease through downregulation of an interleukin-1β-dependent glycolytic pathway in Th17 cells. Mediat Inflamm. 2015;2015:631384.

    Google Scholar 

  48. Cooke KR, Olkiewicz K, Erickson N, Ferrara JL. The role of endotoxin and the innate immune response in the pathophysiology of acute graft versus host disease. J Endotoxin Res. 2002;8:441–8.

    Article  CAS  Google Scholar 

  49. Bertz H, Afting M, Kreisel W, Duffner U, Greinwald R, Finke J. Feasibility and response to budesonide as topical corticosteroid therapy for acute intestinal GVHD. Bone Marrow Transpl. 1999;24:1185–9.

    Article  CAS  Google Scholar 

  50. Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system. Nature. 2012;489:231–41.

    Article  CAS  Google Scholar 

  51. Brown EM, Sadarangani M, Finlay BB. The role of the immune system in governing host-microbe interactions in the intestine. Nat Immunol. 2013;14:660–7.

    Article  CAS  Google Scholar 

  52. Eriguchi Y, Takashima S, Oka H, Shimoji S, Nakamura K, Uryu H, et al. Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of alpha-defensins. Blood. 2012;120:223–31.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Hematology, Saitama Medical Center, Jichi Medical University, Shimotsuke, Japan

    Kazuaki Kameda, Shun-ichi Kimura, Yukiko Misaki, Kazuki Yoshimura, Ayumi Gomyo, Jin Hayakawa, Masaharu Tamaki, Machiko Kusuda, Yu Akahoshi, Tomotaka Ugai, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Aki Tanihara, Hidenori Wada, Miki Sato, Kiriko Terasako-Saito, Misato Kikuchi, Hideki Nakasone, Shinichi Kako & Yoshinobu Kanda

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Kameda, K., Kimura, Si., Misaki, Y. et al. Associations between febrile neutropenia-related parameters and the risk of acute GVHD or non-relapse mortality after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 54, 707–716 (2019). https://doi.org/10.1038/s41409-018-0330-2

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