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Ferritin as an early marker of graft rejection after allogeneic hematopoietic stem cell transplantation in pediatric patients

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Abstract

Diagnosis of adverse events following hematopoietic stem cell transplantation (HSCT) is mainly assigned to clinical symptoms or biopsies and thus rather unspecific and/or invasive. Studies indicate a distinct role of serum ferritin in HSCT and its correlation with adverse events such as graft-versus-host disease (GvHD), veno-occlusive disease (VOD), or infections. However, published data on the relevance of ferritin as a prognostic marker for post-transplant adverse events is rare, especially in pediatric patients. The present study analyzes ferritin plasma concentrations of 138 pediatric patients after HSCT between 2007 and 2010 including the control group (n = 21). Given the initial results regarding ferritin as a significant predictor for acute graft rejection after allogeneic HSCT in 9 of the 138 pediatric patients, serum ferritin of all pediatric patients (n = 27) who experienced graft rejection between 2007 and 2014 was analyzed. In addition, laboratory parameters including C-reactive protein (CRP), lactate dehydrogenase (LDH), fibrinogen, and d-dimer as possible differentiation markers for graft rejection were determined. In 24 (88.9 %) of the 27 pediatric patients with graft rejection, a significant increase of ferritin levels was observed 1 to 7 days prior to (P < 0.0001) and at the time of graft rejection (P < 0.0001). Moreover, there was an increase of d-dimer, CRP, LDH, and fibrinogen 1–7 days before graft rejection. Ferritin increased significantly at time of VOD (P = 0.0067), at time of intestinal (P < 0.0001) and skin GvHD (P < 0.0001), and at time of sepsis (P = 0.0005) and bacteremia (P = 0.0029). Ferritin might serve as a readily available identification marker for differentiation and identification of adverse events after HSCT in combination with other laboratory markers.

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References

  1. Baker KS, Allen RD, Roths JB, Sidman CL (1995) Kinetic and organ-specific patterns of cytokine expression in acute graft-versus-host disease. Bone Marrow Transplant 15(4):595–603

    PubMed  CAS  Google Scholar 

  2. Fujita A, Ihira M, Suzuki R, Enomoto Y, Sugiyama H, Sugata K, Suga S, Asano Y, Yagasaki H, Kojima S, Matsumoto K, Kato K, Yoshikawa T (2008) Elevated serum cytokine levels are associated with human herpesvirus 6 reactivation in hematopoietic stem cell transplantation recipients. J Infect 57(3):241–248. doi:10.1016/j.jinf.2008.06.014

    Article  PubMed  Google Scholar 

  3. Min CK, Lee WY, Min DJ, Lee DG, Kim YJ, Park YH, Kim HJ, Lee S, Kim DW, Lee JW, Min WS, Kim CC (2001) The kinetics of circulating cytokines including IL-6, TNF-alpha, IL-8 and IL-10 following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 28(10):935–940. doi:10.1038/sj.bmt.1703258

    Article  PubMed  CAS  Google Scholar 

  4. Schots R, Kaufman L, Van Riet I, Ben Othman T, De Waele M, Van Camp B, Demanet C (2003) Proinflammatory cytokines and their role in the development of major transplant-related complications in the early phase after allogeneic bone marrow transplantation. Leukemia 17(6):1150–1156. doi:10.1038/sj.leu.2402946

    Article  PubMed  CAS  Google Scholar 

  5. Shulman HM, McDonald GB, Matthews D, Doney KC, Kopecky KJ, Gauvreau JM, Thomas ED (1980) An analysis of hepatic venocclusive disease and centrilobular hepatic degeneration following bone marrow transplantation. Gastroenterology 79(6):1178–1191

    PubMed  CAS  Google Scholar 

  6. Remberger M, Jaksch M, Uzunel M, Mattsson J (2003) Serum levels of cytokines correlate to donor chimerism and acute graft-vs.-host disease after haematopoietic stem cell transplantation. Eur J Haematol 70(6):384–391

    Article  PubMed  CAS  Google Scholar 

  7. Takatsuka H, Takemoto Y, Okamoto T, Fujimori Y, Tamura S, Wada H, Okada M, Yamada S, Kanamaru A, Kakishita E (1999) Predicting the severity of graft-versus-host disease from interleukin-10 levels after bone marrow transplantation. Bone Marrow Transplant 24(9):1005–1007. doi:10.1038/sj.bmt.1702010

    Article  PubMed  CAS  Google Scholar 

  8. Fowler DH, Foley J, Whit-Shan Hou J, Odom J, Castro K, Steinberg SM, Gea-Banacloche J, Kasten-Sportes C, Gress RE, Bishop MR (2004) Clinical "cytokine storm" as revealed by monocyte intracellular flow cytometry: correlation of tumor necrosis factor alpha with severe gut graft-versus-host disease. Clin Gastroenterol Hepatol 2(3):237–245

    Article  PubMed  CAS  Google Scholar 

  9. Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JL (1997) Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood 90(8):3204–3213

    PubMed  CAS  Google Scholar 

  10. Imamura M, Hashino S, Kobayashi H, Kubayashi S, Hirano S, Minagawa T, Tanaka J, Fujii Y, Kobayashi M, Kasai M et al (1994) Serum cytokine levels in bone marrow transplantation: synergistic interaction of interleukin-6, interferon-gamma, and tumor necrosis factor-alpha in graft-versus-host disease. Bone Marrow Transplant 13(6):745–751

    PubMed  CAS  Google Scholar 

  11. Visentainer JE, Lieber SR, Persoli LB, Vigorito AC, Aranha FJ, de Brito Eid KA, Oliveira GB, Miranda EC, de Souza CA (2003) Serum cytokine levels and acute graft-versus-host disease after HLA-identical hematopoietic stem cell transplantation. Exp Hematol 31(11):1044–1050

    Article  PubMed  CAS  Google Scholar 

  12. Remberger M, Ringden O (1995) Increased levels of soluble interleukin-2 receptor in veno-occlusive disease of the liver after allogenic bone marrow transplantation. Transplantation 60(11):1293–1299

    Article  PubMed  CAS  Google Scholar 

  13. Prat C, Sancho JM, Dominguez J, Xicoy B, Gimenez M, Ferra C, Blanco S, Lacoma A, Ribera JM, Ausina V (2008) 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 49(9):1752–1761. doi:10.1080/10428190802258956

    Article  PubMed  CAS  Google Scholar 

  14. Diepold M, Noellke P, Duffner U, Kontny U, Berner R (2008) Performance of Interleukin-6 and interleukin-8 serum levels in pediatric oncology patients with neutropenia and fever for the assessment of low-risk. BMC Infect Dis 8:28. doi:10.1186/1471-2334-8-28

    Article  PubMed  PubMed Central  Google Scholar 

  15. Grossekatthöfer M, Guclu ED, Lawitschka A, Matthes-Martin S, Mann G, Minkov M, Peters C, Seidel MG (2013) Ferritin concentrations correlate to outcome of hematopoietic stem cell transplantation but do not serve as biomarker of graft-versus-host disease. Ann Hematol 92(8):1121–1128. doi:10.1007/s00277-013-1737-x

    Article  PubMed  Google Scholar 

  16. Pullarkat V, Blanchard S, Tegtmeier B, Dagis A, Patane K, Ito J, Forman SJ (2008) Iron overload adversely affects outcome of allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 42(12):799–805. doi:10.1038/bmt.2008.262

    Article  PubMed  CAS  Google Scholar 

  17. Kataoka K, Nannya Y, Hangaishi A, Imai Y, Chiba S, Takahashi T, Kurokawa M (2009) Influence of pretransplantation serum ferritin on nonrelapse mortality after myeloablative and nonmyeloablative allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 15(2):195–204. doi:10.1016/j.bbmt.2008.11.012

    Article  PubMed  Google Scholar 

  18. Armand P, Kim HT, Cutler CS, Ho VT, Koreth J, Alyea EP, Soiffer RJ, Antin JH (2007) Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 109(10):4586–4588. doi:10.1182/blood-2006-10-054924

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Kanda J, Mizumoto C, Ichinohe T, Kawabata H, Saito T, Yamashita K, Kondo T, Takakura S, Ichiyama S, Uchiyama T, Ishikawa T (2011) Pretransplant serum ferritin and C-reactive protein as predictive factors for early bacterial infection after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 46(2):208–216. doi:10.1038/bmt.2010.108

    Article  PubMed  CAS  Google Scholar 

  20. Sivgin S, Baldane S, Kaynar L, Kurnaz F, Pala C, Ozturk A, Cetin M, Unal A, Eser B (2012) Pretransplant serum ferritin level may be a predictive marker for outcomes in patients having undergone allogeneic hematopoietic stem cell transplantation. Neoplasma 59(2):183–190

    Article  PubMed  CAS  Google Scholar 

  21. Arndt C, Beck JF, Gruhn B (2014) A pediatric prognostic score for patients undergoing allogeneic hematopoietic stem cell transplantation. Eur J Haematol 93(6):509–515. doi:10.1111/ejh.12390

    Article  PubMed  CAS  Google Scholar 

  22. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, Hardin BJ, Shulman HM, Clift RA (1993) Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 118(4):255–267

    Article  PubMed  CAS  Google Scholar 

  23. McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED (1984) Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 4(1):116–122

    Article  PubMed  CAS  Google Scholar 

  24. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, Lerner KG, Thomas ED (1974) Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 18(4):295–304

    Article  PubMed  CAS  Google Scholar 

  25. Goldstein B, Giroir B, Randolph A (2005) International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 6(1):2–8. doi:10.1097/01.pcc.0000149131.72248.e6

    Article  PubMed  Google Scholar 

  26. Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z, Fiere D, Lortholary O, Maertens J, Meis JF, Patterson TF, Ritter J, Selleslag D, Shah PM, Stevens DA, Walsh TJ (2002) Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 34(1):7–14. doi:10.1086/323335

    Article  PubMed  CAS  Google Scholar 

  27. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Pappas PG, Maertens J, Lortholary O, Kauffman CA, Denning DW, Patterson TF, Maschmeyer G, Bille J, Dismukes WE, Herbrecht R, Hope WW, Kibbler CC, Kullberg BJ, Marr KA, Munoz P, Odds FC, Perfect JR, Restrepo A, Ruhnke M, Segal BH, Sobel JD, Sorrell TC, Viscoli C, Wingard JR, Zaoutis T, Bennett JE (2008) Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46(12):1813–1821. doi:10.1086/588660

    Article  PubMed  PubMed Central  Google Scholar 

  28. Spitzer TR (2001) Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant 27(9):893–898. doi:10.1038/sj.bmt.1703015

    Article  PubMed  CAS  Google Scholar 

  29. Schmid I, Stachel D, Pagel P, Albert MH (2008) Incidence, predisposing factors, and outcome of engraftment syndrome in pediatric allogeneic stem cell transplant recipients. Biol Blood Marrow Transplant 14(4):438–444. doi:10.1016/j.bbmt.2008.02.002

    Article  PubMed  Google Scholar 

  30. Ahmed MS, Jadhav AB, Hassan A, Meng QH (2012) Acute phase reactants as novel predictors of cardiovascular disease. ISRN Inflamm 2012:953461. doi:10.5402/2012/953461

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Koskenkorva-Frank TS, Weiss G, Koppenol WH, Burckhardt S (2013) The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: insights into the potential of various iron therapies to induce oxidative and nitrosative stress. Free Radic Biol Med 65:1174–1194. doi:10.1016/j.freeradbiomed.2013.09.001

    Article  PubMed  CAS  Google Scholar 

  32. Kell DB, Pretorius E (2014) Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics 6(4):748–773. doi:10.1039/c3mt00347g

    Article  PubMed  CAS  Google Scholar 

  33. Tanaka M, Tachibana T, Numata A, Takasaki H, Matsumoto K, Maruta A, Ishigatsubo Y, Kanamori H (2012) A prognostic score with pretransplant serum ferritin and disease status predicts outcome following reduced-intensity SCT. Bone Marrow Transplant 47(4):596–597. doi:10.1038/bmt.2011.122

    Article  PubMed  CAS  Google Scholar 

  34. Altes A, Remacha AF, Sureda A, Martino R, Briones J, Canals C, Brunet S, Sierra J, Gimferrer E (2002) Iron overload might increase transplant-related mortality in haematopoietic stem cell transplantation. Bone Marrow Transplant 29(12):987–989. doi:10.1038/sj.bmt.1703570

    Article  PubMed  CAS  Google Scholar 

  35. Paczesny S, Levine JE, Braun TM, Ferrara JL (2009) Plasma biomarkers in graft-versus-host disease: a new era? Biol Blood Marrow Transplant 15(1 Suppl):33–38. doi:10.1016/j.bbmt.2008.10.027

    Article  PubMed  Google Scholar 

  36. Toubai T, Tanaka J, Paczesny S, Shono Y, Reddy P, Imamura M (2012) Role of cytokines in the pathophysiology of acute graft-versus-host disease (GVHD): are serum/plasma cytokines potential biomarkers for diagnosis of acute GVHD following allogeneic hematopoietic cell transplantation (Allo-HCT)? Curr Stem Cell Res Ther 7(3):229–239

    Article  PubMed  CAS  Google Scholar 

  37. Chen YB, Cutler CS (2013) Biomarkers for acute GVHD: can we predict the unpredictable? Bone Marrow Transplant 48(6):755–760. doi:10.1038/bmt.2012.143

    Article  PubMed  CAS  Google Scholar 

  38. Morado M, Ojeda E, Garcia-Bustos J, Aguado MJ, Arrieta R, Quevedo E, Navas A, Hernandez-Navarro F (2000) BMT: serum ferritin as risk factor for veno-occlusive disease of the liver. Prospective cohort study. Hematology 4(6):505–512

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank the Stefan-Morsch-Stiftung for the financial support.

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Author notes

  1. Michaela Döring

    Present address: Dr. von Hauner’sches Kinderspital, Pediatric Hematology, Oncology and Stem Cell Transplantation, Ludwig-Maximilians-University München, Lindwurmstrasse 4, 80337, Munich, Germany

Authors and Affiliations

  1. Department I – General Paediatrics, Hematology/Oncology, Children’s Hospital, University Hospital Tuebingen, Hoppe-Seyler-Str. 1, 72076, Tuebingen, Germany

    Michaela Döring, Karin Melanie Cabanillas Stanchi, Judith Feucht, Manon Queudeville, Heiko-Manuel Teltschik, Peter Lang, Tobias Feuchtinger & Rupert Handgretinger

  2. Dr. von Hauner’sches Kinderspital, Pediatric Hematology, Oncology and Stem Cell Transplantation, Ludwig-Maximilians-University München, Lindwurmstrasse 4, 80337, Munich, Germany

    Tobias Feuchtinger

  3. Department of Paediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

    Ingo Müller

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  1. Michaela Döring
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Correspondence to Michaela Döring.

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This retrospective analysis was conducted in accordance with the Declaration of Helsinki and was performed under the waiver for retrospective anonymized studies in accordance with the ethics regulations of the Independent Ethics Committee of the University of Tübingen, Germany.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

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Döring, M., Cabanillas Stanchi, K.M., Feucht, J. et al. Ferritin as an early marker of graft rejection after allogeneic hematopoietic stem cell transplantation in pediatric patients. Ann Hematol 95, 311–323 (2016). https://doi.org/10.1007/s00277-015-2560-3

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