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.

  • Review
  • Published:

Engraftment syndrome: double-edged sword of hematopoietic cell transplants

Bone Marrow Transplantation volume 50, pages 469–475 (2015)Cite this article

Subjects

Abstract

Engraftment syndrome (ES) after hematopoietic cell transplantation (HCT) is increasingly diagnosed. Common features include fever, pulmonary vascular leak, rash and organ dysfunction. Different diagnostic criteria likely account for the wide (7–90%) range of reported incidences. ES typically occurs within 4 days of granulocyte recovery although a recently described seemingly similar syndrome occurs >1 week before granulocyte recovery after umbilical cord blood cell transplants. Although the clinical manifestations of ES may be identical to those of acute GVHD, ES also has been well described in patients without acute GVHD. The data are conflicting as to whether ES is associated with a higher nonrelapse mortality and worse survival after HCT. The pathophysiology of ES is unclear, but endothelial injury and activated granulocytes in the setting of proinflammatory cytokines may be important. ES typically is self-limited, but, like acute GVHD, responds to corticosteroids. Because ES and acute GVHD may have overlapping features and response to therapy, these disease processes may often not be distinct events. Moreover, features of ES may overlap with those of drug- and radiation-induced toxicities and infection. Further research to better characterize the clinical spectrum and etiology of ES and to determine its relationship to GVHD is needed.

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

Similar content being viewed by others

References

  1. Spitzer TR . Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 27: 893–8982.

    Article  CAS  PubMed  Google Scholar 

  2. Maiolino A, Biasoli I, Lima J, Portugal AC, Pulcheri W, Nucci M . Engraftment syndrome following autologous hematopoietic stem cell transplantation: definition of diagnostic criteria. Bone Marrow Transplant 2003; 31: 393–397.

    Article  CAS  PubMed  Google Scholar 

  3. Carreras E, Fernandez-Aviles F, Silva L, Guerrero M, Fernandez de Larrea C, Martinez C et al. Engraftment syndrome after auto-SCT: analysis of diagnostic criteria and risk factors in a large series from a single center. Bone Marrow Transplant 2010; 45: 1417–1422.

    Article  CAS  PubMed  Google Scholar 

  4. Cahill RA, Spitzer TR, Mazumder A . Marrow engraftment and clinical manifestations of capillary leak syndrome. Bone Marrow Transplant 1996; 18: 177–184.

    CAS  PubMed  Google Scholar 

  5. Nurnberger W, Willers R, Burcach S, Gobel U . Risk factors for capillary leakage syndrome after bone marrow transplantation. Ann Hematol 1997; 74: 221–224.

    Article  CAS  PubMed  Google Scholar 

  6. de Arriba F, Corral J, Ayala F, Heras I, Moraleda JM, Osma MM et al. Autoaggression syndrome resembling acute graft-versus-host disease grade IV after autologous peripheral blood stem cell transplantation for breast cancer. Bone Marrow Transplant 1999; 23: 621–624.

    Article  CAS  PubMed  Google Scholar 

  7. Moreb JS, Kubilis PS, Mullins DL, Myers L, Youngblood M, Hutcheson C . Increased frequency of autoaggression syndrome associated with autologous stem cell transplantation in breast cancer patients. Bone Marrow Transplant 1997; 19: 101–106.

    Article  CAS  PubMed  Google Scholar 

  8. Miller C, Hayashi R, Vogelsang GB . Aseptic shock syndrome after bone marrow transplantation. Blood 1992; 80: 140a.

    Google Scholar 

  9. Chang L, Frame D, Braun T, Gatza E, Hanauer DA, Zhao S et al. Engraftment syndrome after allogeneic hematopoietic cell transplantation predicts poor outcomes. Biol Blood Marrow Transplant 2014; 20: 1407–1417.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Gorak E, Geller N, Srinivasan R, Espinoza-Delgado I, Donohue T, Barrett AJ et al. Engraftment syndrome after nonmyeloablative allogeneic hematopoietic stem cell transplantation: incidence and effects on survival. Biol Blood Marrow Transplant 2005; 11: 542–550.

    Article  PubMed  Google Scholar 

  11. Omer AK, Kim HT, Yalamarti B, McAfee S, Dey BR, Ballen KK et al. Engraftment syndrome after allogeneic hematopoietic cell transplantation in adults. Am J Hematol 2014; 89: 698–705.

    Article  PubMed  Google Scholar 

  12. Khan SA, Gaa B, Pollock BH, Shea B, Reddy V, Wingard J et al. Engraftment syndrome in breast cancer patients after stem cell transplantation is associated with poor long-term survival. Bone Marrow Transplant 2001; 7: 433–438.

    Article  CAS  Google Scholar 

  13. Schmid I, Stachel D, Pagel P, Albert MH . Incidence, predisposing factors, and outcome of engraftment syndrome in pediatric allogeneic stem cell transplant recipients. Biol Blood Marrow Transplant. 2008; 14: 438–444.

    Article  PubMed  Google Scholar 

  14. Madero L, Vincent MG, Sevilla J, Prudencio M, Rodriguez F, Diaz MA . Engraftment syndrome in children undergoing autologous peripheral blood progenitor cell transplantation. Bone Marrow Transplant 2002; 30: 355–358.

    Article  CAS  PubMed  Google Scholar 

  15. Koreth J, Biernacki M, Aldridge J, Kim HT, Alyea EP 3rd, Armand P et al. Syngeneic donor hematopoietic stem cell transplantation is associated with high rates of engraftment syndrome. Biol Blood Marrow Transplant 2011; 17: 421–428.

    Article  PubMed  Google Scholar 

  16. Hess AD, Jones RC, Santos GW . Autologous graft-vs-host disease: mechanisms and potential therapeutic effect. Bone Marrow Transplant 1993; 12: S65–S69.

    PubMed  Google Scholar 

  17. Kline J, Subbiah S, Lazarus HM, van Besien K . Autologous graft-versus-host disease: harnessing anti-tumor immunity through impaired self-tolerance. Bone Marrow Transplant 2008; 41: 505–513.

    Article  CAS  PubMed  Google Scholar 

  18. Lazarus HM, Sommers SR, Arfons LM, Fu P, Ataergin SA, Kaye NM et al. Spontaneous autologous graft-versus-host disease in plasma cell myeloma autograft recipients: flow cytometric analysis of hematopoietic progenitor cell grafts. Biol Blood Marrow Transplant 2011; 17: 970–978.

    Article  CAS  PubMed  Google Scholar 

  19. Lee CK, Gingrich RD, Hohl RJ, Ajram KA . Engraftment syndrome in autologous bone marrow and peripheral stem cell transplantation. Bone Marrow Transplant 1995; 16: 175–182.

    CAS  PubMed  Google Scholar 

  20. Ravoet C, Feremans W, Husson B, Majois F, Kentos A, Lambermont M et al. Clinical evidence for an engraftment syndrome associated with early and steep neutrophil recovery after autologous blood stem cell transplantation. Bone Marrow Transplant 1996; 18: 943–947.

    CAS  PubMed  Google Scholar 

  21. Edenfield WJ, Moores LK, Goodwin G, Lee N . An engraftment syndrome in autologous stem cell transplantation related to mononuclear cell dose. Bone Marrow Transplant 2000; 25: 405–409.

    Article  CAS  PubMed  Google Scholar 

  22. Oyama Y, Cohen B, Traynor A, Brush M, Rodriguez J, Burt RK . Engraftment syndrome: a common cause for rash and fever following hematopoietic stem cell transplantation for multiple sclerosis. Bone Marrow Transplant 2002; 29: 81–85.

    Article  CAS  PubMed  Google Scholar 

  23. Akasheh M, Eastwood D, Vesole DH . Engraftment syndrome after autologous hematopoietic stem cell transplant supported by granulocyte-colony-stimulating factor (G-CSF) versus granulocyte-macrophage colony-stimulating factor (GM-CSF). Bone Marrow Transplant 2003; 31: 113–116.

    Article  CAS  PubMed  Google Scholar 

  24. Dispenzieri A, Lacy MQ, Hayman SR, Kumar SK, Buadi F, Dingli D et al. Peripheral blood stem cell transplant for POEMS syndrome is associated with high rates of engraftment syndrome. Eur J Haematol 2008; 80: 397–406.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Marin D, Berrade J, Ferra C, Mateu A, Berlanga J, Salar A et al. Engraftment syndrome and survival after respiratory failure post-bone marrow transplantation. Intensive Care Med 1998; 24: 732–735.

    Article  CAS  PubMed  Google Scholar 

  26. Foncillas MA, Diaz MA, Sevilla J, Gonzalez Vincent M, Fernandez-Plaza S, Perez A et al. Engraftment syndrome emerges as the main cause of transplant-related mortality in pediatric patients receiving autologous peripheral blood progenitor cell transplantation. J Pediatr Hematol Oncol 2004; 26: 492–496.

    Article  PubMed  Google Scholar 

  27. Gonzalez-Vincent M, Ramirez M, Sevilla J, Perez A, Fernandez S, Madero L et al. Engraftment syndrome after autologous peripheral blood progenitor cell transplantation in pediatric patients: a prospective evaluation of risk factors and outcome. Bone Marrow Transplant 2004; 34: 1051–1055.

    Article  Google Scholar 

  28. Saliba RM, de Lima M, Giralt S, Andersson B, Khouri IF, Hosig C et al. Hyperacute GVHD: risk factors, outcomes and clinical implications. Blood 2007; 109: 2751–2758.

    CAS  PubMed  Google Scholar 

  29. Kim DH, Sohn SK, Kim JG, Suh JS, Lee KS, Lee KB et al. Clinical impact of hyperacute graft-versus-host-disease on results of allogeneic stem cell transplantation. Bone Marrow Transplant. 2004; 33: 1025–1030.

    Article  CAS  PubMed  Google Scholar 

  30. Nishio N, Yagasaki H, Takahashi Y, Hama A, Muramatsu H, Tanaka M et al. Engraftment syndrome following allogeneic hematopoietic stem cell transplantation in children. Pediatr Transplant 2009; 13: 831–837.

    Article  CAS  PubMed  Google Scholar 

  31. Hong KT, Kang HJ, Kim NH, Kim MS, Lee JW, Kim H et al. Peri-engraftment syndrome in allogeneic hematopoietic SCT. Bone Marrow Transplant 2013; 48: 523–528.

    Article  CAS  PubMed  Google Scholar 

  32. Antin J, Ferrara L . Cytokine dysregulation and acute graft versus host disease. Blood 1992; 80: 2964–2968.

    CAS  PubMed  Google Scholar 

  33. Toubai T, Tanaka J, Paczesny S, Shono Y, Reddy P, Imamura M . 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 (alloHCT)? Curr Stem Cell Res Ther 2012; 7: 229–239.

    Article  CAS  PubMed  Google Scholar 

  34. Takatsuka H, Takemoto Y, Yamada S, Wada H, Tamura S, Fujimori Y et al. Complications after bone marrow transplantation are manifestations of systemic inflammatory response syndrome. Bone Marrow Transplant 2000; 26: 419–426.

    Article  CAS  PubMed  Google Scholar 

  35. Rabinowitz J, Petros WP, Stuart AR, Peters WP . Characterization of endogenous cytokine concentrations after high-dose chemotherapy with autologous bone marrow support. Blood 1993; 81: 2452–2459.

    CAS  PubMed  Google Scholar 

  36. Mossad S, Kalaycio M, Sobecks R, Pohlman B, Andresen S, Avery R et al. Steroids prevent engraftment syndrome after autologous hematopoietic stem cell transplantation without increasing the risk of infection. Bone Marrow Transplant 2005; 35: 375–381.

    Article  CAS  PubMed  Google Scholar 

  37. Salat C, Holler E, Schleuning M, Eisele B, Reinhardt B, Kolb H et al. Levels of the terminal complement complex, C3a-desArg and C1-inhibitor in adult patients with capillary leak syndrome following bone marrow transplantation. Ann Hematol 1995; 71: 271–274.

    Article  CAS  PubMed  Google Scholar 

  38. Nurnberger W, Michelmann I, Burdach S, Gobel U . Endothelial dysfunction after bone marrow transplantation: increase of soluble thrombomodulin and PAI-1 in patients with multiple transplant-related complication. Ann Hematol 1998; 76: 61–65.

    Article  CAS  PubMed  Google Scholar 

  39. Ikezoe T, Takeuchi A, Taniguchi A, Togitani K, Yokoyama A . Recombinant human soluble thrombomodulin counteracts capillary leakage associated with engraftment syndrome. Bone Marrow Transplant 2011; 46: 616–618.

    Article  CAS  PubMed  Google Scholar 

  40. Chen YB, Cutler CS . Biomarkers for acute GVHD: can we predict the unpredictable? Bone Marrow Transplant 2013; 48: 755–760.

    Article  CAS  PubMed  Google Scholar 

  41. Lee Y-H, Lim YJ, Kim JY, Kim YD, Lee SW . Pre-engraftment syndrome in hematopoietic stem cell transplantation. J Korean Med Sci 2008; 23: 98–103.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Patel KJ, Rice RD, Hawke R, Abboud M, Heller G, Scaradavou A et al. Pre-engraftment syndrome after double-unit cordblood transplantation: a distinct syndrome not associated with acute graft-versus-host disease. Biol Blood Marrow Transplant 2010; 16: 435–440.

    Article  PubMed  Google Scholar 

  43. Wang X, Liu H, Li L, Geng L, Ding K, Liu X et al. Pre-engraftment syndrome after unrelated donor umbilical cord blood transplantation in patients with hematologic malignancies. Eur J Haematol 2012; 88: 39–45.

    Article  CAS  PubMed  Google Scholar 

  44. Brownback KR, Simpson SQ, McGuirk JP, Lin TL, Abhyankar S, Ganguly S et al. Pulmonary manifestations of the pre-engraftment syndrome after umbilical cord blood transplantation. Ann Hematol 2013; 93: 847–854.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Kanda J, Kaynar L, Kanda Y, Prasad VK, Parikh SH, Lan L et al. Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: risk factors and response to treatment. Bone Marrow Transplant 2013; 48: 926–932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Park M, Lee SH, Lee YH . Pre-engraftment syndrome after unrelated cord blood transplantation: a predictor of engraftment and acute graft-versus-host disease. Biol Blood Marrow Transplant 2013; 19: 640–646.

    Article  PubMed  Google Scholar 

  47. Farris AB, Taheri D, Kawai T, Fazlollahi L, Wong W, Tolkoff-Rubin N et al. Acute renal endothelial injury during marrow recovery in a cohort of combined kidney and marrow allografts. Am J Transplant 2011; 11: 1464–1477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Colby C, McAfee S, Sackstein R, Dey B, Saidman S, Sachs DH et al. Engraftment syndrome following non-myeloablative conditioning therapy and HLA-matched bone marrow transplantation (BMT) for hematologic malignancy (HM). Blood 2000; 96: 520a.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Bone Marrow Transplant Program, Massachusetts General Hospital, Boston, MA, USA

    T R Spitzer

Authors
  1. T R Spitzer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T R Spitzer.

Ethics declarations

Competing interests

The author declares no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Spitzer, T. Engraftment syndrome: double-edged sword of hematopoietic cell transplants. Bone Marrow Transplant 50, 469–475 (2015). https://doi.org/10.1038/bmt.2014.296

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2014.296

This article is cited by

Search

Advanced search

Quick links