Graft Versus Host Disease (GHVD) in Critically Ill Oncologic Patients

  • Ulas Darda BayraktarEmail author
Reference work entry


Graft-versus-host-disease (GVHD) is the most common life-threatening complication of allogeneic hematopoietic stem cell transplantation (ASCT). More than 40% of ASCT patients admitted to the intensive care unit (ICU) has GVHD, which has been reported to be associated with worsened ICU outcomes. GVHD commonly involves mucocutaneous tissues, gastrointestinal tract, and liver, manifesting itself in rash, diarrhea, anorexia, and cholestasis. Chronic GVHD may also involve lungs directly causing bronchiolitis obliterans which may complicate mechanical ventilation. GVHD prophylaxis improves survival in ASCT patients. Calcineurin inhibitors are the backbone of GVHD prophylaxis and are frequently combined with methotrexate, mycophenolate mofetil, or sirolimus. While corticosteroids are used for the first-line treatment of GVHD, many options exist for steroid-refractory GVHD. Almost all GVHD agents suppress the immune system rendering patients susceptible to bacterial, viral, and fungal infections. The novel T cell selection methods used for GVHD prevention may cause less immunosuppression resulting in improved ICU outcomes. In this chapter, we will focus on the impact of GVHD and its treatment on the management of the critical care patient.


Graft-versus-host-disease Bronchiolitis obliterans T cells Corticosteroids Tacrolimus Cyclosporine Mycophenolate mofetil Sirolimus Methotrexate 


  1. 1.
    Pavletic SZ, Vogelsang GB, Lee SJ. 2014 National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: preface to the series. Biol Blood Marrow Transplant. 2015;21:387–8. Scholar
  2. 2.
    Bayraktar UD, Milton DR, Shpall EJ, Rondon G, Price KJ, Champlin RE, Nates JL. Prognostic index for critically ill allogeneic transplantation patients. Biol Blood Marrow Transplant. 2017;23:991–6. Scholar
  3. 3.
    Bayraktar UD, Nates JL. Intensive care outcomes in adult hematopoietic stem cell transplantation patients. World J Clin Oncol. 2016;7:98–105. Scholar
  4. 4.
    Lengline E, et al. Changes in intensive care for allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2015;50:840–5. Scholar
  5. 5.
    Orvain C, et al. Different impact of the number of organ failures and graft-versus-host disease on the outcome of allogeneic stem cell transplantation recipients requiring intensive care. Transplantation. 2017;101:437–44. Scholar
  6. 6.
    Choi SW, 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. Scholar
  7. 7.
    Koyama M, et al. Recipient nonhematopoietic antigen-presenting cells are sufficient to induce lethal acute graft-versus-host disease. Nat Med. 2011;18: 135–42. Scholar
  8. 8.
    Mathewson ND, et al. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat Immunol. 2016;17:505–13. Scholar
  9. 9.
    Schwab L, et al. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nat Med. 2014;20:648–54. Scholar
  10. 10.
    Shalaby MR, Fendly B, Sheehan KC, Schreiber RD, Ammann AJ. Prevention of the graft-versus-host reaction in newborn mice by antibodies to tumor necrosis factor-alpha. Transplantation. 1989;47: 1057–61.CrossRefGoogle Scholar
  11. 11.
    Socie G, et al. Prognostic value of apoptotic cells and infiltrating neutrophils in graft-versus-host disease of the gastrointestinal tract in humans: TNF and Fas expression. Blood. 2004;103:50–7. Scholar
  12. 12.
    Asai O, Longo DL, Tian ZG, Hornung RL, Taub DD, Ruscetti FW, Murphy WJ. Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation. J Clin Invest. 1998;101:1835–42. Scholar
  13. 13.
    Palathumpat V, Dejbakhsh-Jones S, Holm B, Strober S. Different subsets of T cells in the adult mouse bone marrow and spleen induce or suppress acute graft-versus-host disease. J Immunol. 1992;149:808–17.PubMedGoogle Scholar
  14. 14.
    Ruggeri L, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097–100. Scholar
  15. 15.
    Zeiser R, Blazar BR. Acute graft-versus-host disease - biologic process, prevention, and therapy. N Engl J Med. 2017;377:2167–79. Scholar
  16. 16.
    Jagasia M, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012;119:296–307. Scholar
  17. 17.
    Loiseau P, et al. HLA association with hematopoietic stem cell transplantation outcome: the number of mismatches at HLA-A, -B, -C, -DRB1, or -DQB1 is strongly associated with overall survival. Biol Blood Marrow Transplant. 2007;13:965–74. Scholar
  18. 18.
    Martin PJ, et al. Genome-wide minor histocompatibility matching as related to the risk of graft-versus-host disease. Blood. 2017;129:791–8. Scholar
  19. 19.
    Santos N, et al. UGT2B17 minor histocompatibility mismatch and clinical outcome after HLA-identical sibling donor stem cell transplantation. Bone Marrow Transplant. 2016;51:79–82. Scholar
  20. 20.
    Carlens S, et al. Risk factors for chronic graft-versus-host disease after bone marrow transplantation: a retrospective single centre analysis. Bone Marrow Transplant. 1998;22:755–61. Scholar
  21. 21.
    Gratwohl A, et al. Gender and graft-versus-host disease after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22:1145–6. Scholar
  22. 22.
    Chang YJ, Weng CL, Sun LX, Zhao YT. Allogeneic bone marrow transplantation compared to peripheral blood stem cell transplantation for the treatment of hematologic malignancies: a meta-analysis based on time-to-event data from randomized controlled trials. Ann Hematol. 2012;91:427–37. Scholar
  23. 23.
    Rocha V, Wagner JE Jr, Sobocinski KA, Klein JP, Zhang MJ, Horowitz MM, Gluckman E. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N Engl J Med. 2000;342:1846–54. Scholar
  24. 24.
    Mielcarek M, et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood. 2003;102:756–62. Scholar
  25. 25.
    Przepiorka D, et al. Chronic graft-versus-host disease after allogeneic blood stem cell transplantation. Blood. 2001;98:1695–700.CrossRefGoogle Scholar
  26. 26.
    Aversa F, et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol. 2005;23:3447–54. Scholar
  27. 27.
    Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Blood. 2001;98: 3456–64. Scholar
  28. 28.
    Ratanatharathorn V, et al. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998;92:2303–14.PubMedGoogle Scholar
  29. 29.
    Ringden O, Klaesson S, Sundberg B, Ljungman P, Lonnqvist B, Persson U. Decreased incidence of graft-versus-host disease and improved survival with methotrexate combined with cyclosporin compared with monotherapy in recipients of bone marrow from donors other than HLA identical siblings. Bone Marrow Transplant. 1992;9:19–25.PubMedGoogle Scholar
  30. 30.
    Storb R, et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med. 1986;314:729–35. Scholar
  31. 31.
    Bolwell B, Sobecks R, Pohlman B, Andresen S, Rybicki L, Kuczkowski E, Kalaycio M. A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation. Bone Marrow Transplant. 2004;34:621–5. Scholar
  32. 32.
    Perkins J, et al. A randomized phase II trial comparing tacrolimus and mycophenolate mofetil to tacrolimus and methotrexate for acute graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant. 2010;16:937–47. Scholar
  33. 33.
    Locatelli F, et al. Outcome of children with acute leukemia given HLA-haploidentical HSCT after alphabeta T-cell and B-cell depletion. Blood. 2017;130:677–85. Scholar
  34. 34.
    Shook DR, Triplett BM, Eldridge PW, Kang G, Srinivasan A, Leung W. Haploidentical stem cell transplantation augmented by CD45RA negative lymphocytes provides rapid engraftment and excellent tolerability. Pediatr Blood Cancer. 2015;62: 666–73. Scholar
  35. 35.
    Lee SE, et al. Risk and prognostic factors for acute GVHD based on NIH consensus criteria. Bone Marrow Transplant. 2013;48:587–92. Scholar
  36. 36.
    Kitamura K, et al. Relationship among human herpesvirus 6 reactivation, serum interleukin 10 levels, and rash/graft-versus-host disease after allogeneic stem cell transplantation. J Am Acad Dermatol. 2008;58:802–9. Scholar
  37. 37.
    Strong Rodrigues K, Oliveira-Ribeiro C, de Abreu Fiuza Gomes S, Knobler R. Cutaneous graft-versus-host disease: diagnosis and treatment. Am J Clin Dermatol. 2018;19:33–50. Scholar
  38. 38.
    Glucksberg H, 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.CrossRefGoogle Scholar
  39. 39.
    Malard F, Mohty M. New insight for the diagnosis of gastrointestinal acute graft-versus-host disease. Mediat Inflamm. 2014;2014:701013. Scholar
  40. 40.
    Liao X, Reed SL, Lin GY. Immunostaining detection of cytomegalovirus in gastrointestinal biopsies: clinicopathological correlation at a large academic health system. Gastroenterol Res. 2016;9:92–8. Scholar
  41. 41.
    Matsukuma KE, Wei D, Sun K, Ramsamooj R, Chen M. Diagnosis and differential diagnosis of hepatic graft versus host disease (GVHD). J Gastrointest Oncol. 2016;7:S21–31. Scholar
  42. 42.
    Akpek G, et al. Hepatitic variant of graft-versus-host disease after donor lymphocyte infusion. Blood. 2002;100:3903–7. Scholar
  43. 43.
    Snover DC, Weisdorf SA, Ramsay NK, McGlave P, Kersey JH. Hepatic graft versus host disease: a study of the predictive value of liver biopsy in diagnosis. Hepatology. 1984;4:123–30.CrossRefGoogle Scholar
  44. 44.
    Agusti C, et al. Diffuse alveolar hemorrhage in allogeneic bone marrow transplantation. A postmortem study. Am J Respir Crit Care Med. 1995;151: 1006–10. Scholar
  45. 45.
    Jacobsohn DA, et al. Correlation between NIH composite skin score, patient-reported skin score, and outcome: results from the Chronic GVHD Consortium. Blood. 2012;120:2545–52; quiz 2774. Scholar
  46. 46.
    Aractingi S, Chosidow O. Cutaneous graft-versus-host disease. Arch Dermatol. 1998;134:602–12.CrossRefGoogle Scholar
  47. 47.
    Jagasia MH, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 diagnosis and staging working group report. Biol Blood Marrow Transplant. 2015;21:389–401.e381. Scholar
  48. 48.
    Epstein O, Thomas HC, Sherlock S. Primary biliary cirrhosis is a dry gland syndrome with features of chronic graft-versus-host disease. Lancet. 1980;1: 1166–8.CrossRefGoogle Scholar
  49. 49.
    Song I, Yi CA, Han J, Kim DH, Lee KS, Kim TS, Chung MJ. CT findings of late-onset noninfectious pulmonary complications in patients with pathologically proven graft-versus-host disease after allogeneic stem cell transplant. AJR Am J Roentgenol. 2012;199:581–7. Scholar
  50. 50.
    Williams KM. How I treat bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. Blood. 2017;129:448–55. Scholar
  51. 51.
    Williams KM, et al. Fluticasone, azithromycin, and montelukast treatment for new-onset bronchiolitis obliterans syndrome after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22:710–6. Scholar
  52. 52.
    Vos R, et al. A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation. Eur Respir J. 2011;37:164–72. Scholar
  53. 53.
    Bergeron A, et al. Effect of azithromycin on airflow decline-free survival after allogeneic hematopoietic stem cell transplant: the ALLOZITHRO randomized clinical trial. JAMA. 2017;318:557–66. Scholar
  54. 54.
    Inamoto Y, et al. Incidence, risk factors, and outcomes of sclerosis in patients with chronic graft-versus-host disease. Blood. 2013;121:5098–103. Scholar
  55. 55.
    Stevens AM, Sullivan KM, Nelson JL. Polymyositis as a manifestation of chronic graft-versus-host disease. Rheumatology (Oxford). 2003;42:34–9.CrossRefGoogle Scholar
  56. 56.
    Ruutu T, et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Transplant. 2014;49:168–73. Scholar
  57. 57.
    Bram RJ, Hung DT, Martin PK, Schreiber SL, Crabtree GR. Identification of the immunophilins capable of mediating inhibition of signal transduction by cyclosporin A and FK506: roles of calcineurin binding and cellular location. Mol Cell Biol. 1993;13:4760–9.CrossRefGoogle Scholar
  58. 58.
    Gething MJ, Sambrook J. Protein folding in the cell. Nature. 1992;355:33–45. Scholar
  59. 59.
    Petric R, Freeman D, Wallace C, McDonald J, Stiller C, Keown P. Effect of cyclosporine on urinary prostanoid excretion, renal blood flow, and glomerulotubular function. Transplantation. 1988;45:883–9.CrossRefGoogle Scholar
  60. 60.
    Wong R, et al. Tacrolimus-associated posterior reversible encephalopathy syndrome after allogeneic haematopoietic stem cell transplantation. Br J Haematol. 2003;122:128–34.CrossRefGoogle Scholar
  61. 61.
    Nevill TJ, et al. Influence of post-methotrexate folinic acid rescue on regimen-related toxicity and graft-versus-host disease after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1992;9: 349–54.PubMedGoogle Scholar
  62. 62.
    Morris RE, Hoyt EG, Murphy MP, Eugui EM, Allison AC. Mycophenolic acid morpholinoethylester (RS-61443) is a new immunosuppressant that prevents and halts heart allograft rejection by selective inhibition of T- and B-cell purine synthesis. Transplant Proc. 1990;22:1659–62.PubMedGoogle Scholar
  63. 63.
    Storb R, et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood. 1997;89:3048–54.PubMedGoogle Scholar
  64. 64.
    Hardinger KL, Koch MJ, Brennan DC. Current and future immunosuppressive strategies in renal transplantation. Pharmacotherapy. 2004;24:1159–76.CrossRefGoogle Scholar
  65. 65.
    Cutler C, et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood. 2014;124: 1372–7. Scholar
  66. 66.
    Cutler C, et al. Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation. Blood. 2008;112:4425–31. Scholar
  67. 67.
    Euvrard S, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med. 2012;367:329–39. Scholar
  68. 68.
    Berenbaum MC, Brown IN. Prolongation of homograft survival in mice with single doses of cyclophosphamide. Nature. 1963;200:84.CrossRefGoogle Scholar
  69. 69.
    Brunstein CG, et al. Alternative donor transplantation: results of parallel phase II trials using HLA-mismatched related bone marrow or unrelated umbilical cord blood grafts. Blood. 2011;118:282. Scholar
  70. 70.
    Arango M, Combariza JF. Fever after peripheral blood stem cell infusion in haploidentical transplantation with post-transplant cyclophosphamide. Hematol Oncol Stem Cell Ther. 2017;10:79–84. Scholar
  71. 71.
    Malik SW, Myers JL, DeRemee RA, Specks U. Lung toxicity associated with cyclophosphamide use. Two distinct patterns. Am J Respir Crit Care Med. 1996;154:1851–6. Scholar
  72. 72.
    Braverman AC, Antin JH, Plappert MT, Cook EF, Lee RT. Cyclophosphamide cardiotoxicity in bone marrow transplantation: a prospective evaluation of new dosing regimens. J Clin Oncol. 1991;9:1215–23. Scholar
  73. 73.
    Koura DT, et al. In vivo T cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: a first-in-disease trial. Biol Blood Marrow Transplant. 2013;19:1638–49. Scholar
  74. 74.
    Watkins B, et al. T cell costimulation blockade with abatacept nearly eliminates early severe acute graft versus host disease after HLA-mismatched (7/8 HLA matched) unrelated donor transplant, with a favorable impact on disease-free and overall survival. Paper presented at the 59th ASH annual meeting. 2017.Google Scholar
  75. 75.
    Champlin RE, et al. T-cell depletion of bone marrow transplants for leukemia from donors other than HLA-identical siblings: advantage of T-cell antibodies with narrow specificities. Blood. 2000;95: 3996–4003.PubMedGoogle Scholar
  76. 76.
    Keever CA, et al. Immune reconstitution following bone marrow transplantation: comparison of recipients of T-cell depleted marrow with recipients of conventional marrow grafts. Blood. 1989;73: 1340–50.PubMedGoogle Scholar
  77. 77.
    Marmont AM, et al. T-cell depletion of HLA-identical transplants in leukemia. Blood. 1991;78:2120–30.PubMedGoogle Scholar
  78. 78.
    Bayraktar UD, et al. Ex vivo T cell-depleted versus unmodified allografts in patients with acute myeloid leukemia in first complete remission. Biol Blood Marrow Transplant. 2013;19:898–903. Scholar
  79. 79.
    Walker I, et al. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol. 2016;17:164–73. Scholar
  80. 80.
    Di Ianni M, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117:3921–8. Scholar
  81. 81.
    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 long-term follow-up of an open-label prospective randomized trial. Blood. 1999;93:3267–75.CrossRefGoogle Scholar
  82. 82.
    Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science. 1995;270:286–90.CrossRefGoogle Scholar
  83. 83.
    Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr. Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science. 1995;270:283–6.CrossRefGoogle Scholar
  84. 84.
    Zhang G, Zhang L, Duff GW. A negative regulatory region containing a glucocorticosteroid response element (nGRE) in the human interleukin-1beta gene. DNA Cell Biol. 1997;16:145–52. Scholar
  85. 85.
    Chao NJ, et al. Equivalence of 2 effective graft-versus-host disease prophylaxis regimens: results of a prospective double-blind randomized trial. Biol Blood Marrow Transplant. 2000;6:254–61.CrossRefGoogle Scholar
  86. 86.
    De Jong CN, Saes L, Klerk CPW, Van der Klift M, Cornelissen JJ, Broers AEC. Etanercept for steroid-refractory acute graft-versus-host disease: a single center experience. PLoS One. 2017;12:e0187184. Scholar
  87. 87.
    Korngold R, Marini JC, de Baca ME, Murphy GF, Giles-Komar J. Role of tumor necrosis factor-alpha in graft-versus-host disease and graft-versus-leukemia responses. Biol Blood Marrow Transplant. 2003;9:292–303.CrossRefGoogle Scholar
  88. 88.
    Levine JE, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood. 2008;111:2470–5. Scholar
  89. 89.
    van Groningen LF, Liefferink AM, de Haan AF, Schaap NP, Donnelly JP, Blijlevens NM, van der Velden WJ. Combination therapy with Inolimomab and Etanercept for severe steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2016;22:179–82. Scholar
  90. 90.
    Bolanos-Meade J, et al. Pentostatin in steroid-refractory acute graft-versus-host disease. J Clin Oncol. 2005;23:2661–8. Scholar
  91. 91.
    Alousi AM, et al. Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network. Blood. 2009;114:511–7. Scholar
  92. 92.
    Verstovsek S, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799–807. Scholar
  93. 93.
    Ma HH, et al. Sequential activation of inflammatory signaling pathways during graft-versus-host disease (GVHD): early role for STAT1 and STAT3. Cell Immunol. 2011;268:37–46. Scholar
  94. 94.
    Laurence A, et al. STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. Immunity. 2012;37:209–22. Scholar
  95. 95.
    Zeiser R, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015;29:2062–8. Scholar
  96. 96.
    Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc. 2011;86:1188–91. Scholar
  97. 97.
    Byrd JC, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32–42. Scholar
  98. 98.
    Miklos D, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130:2243–50. Scholar
  99. 99.
    Mock J, et al. Risk of major bleeding with Ibrutinib. Clin Lymphoma Myeloma Leuk. 2018;18:755. Scholar
  100. 100.
    Brown JR, et al. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017;102:1796–805. Scholar
  101. 101.
    Gorgun G, Miller KB, Foss FM. Immunologic mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease. Blood. 2002;100:941–7. Scholar
  102. 102.
    Kapoor N, Pelligrini AE, Copelan EA, Cunningham I, Avalos BR, Klein JL, Tutschka PJ. Psoralen plus ultraviolet A (PUVA) in the treatment of chronic graft versus host disease: preliminary experience in standard treatment resistant patients. Semin Hematol. 1992;29:108–12.PubMedGoogle Scholar
  103. 103.
    Fauci AS, Dale DC, Balow JE. Glucocorticosteroid therapy: mechanisms of action and clinical considerations. Ann Intern Med. 1976;84:304–15.CrossRefGoogle Scholar
  104. 104.
    Butler WT, Rossen RD. Effects of corticosteroids on immunity in man. I. Decreased serum IgG concentration caused by 3 or 5 days of high doses of methylprednisolone. J Clin Invest. 1973;52:2629–40. Scholar
  105. 105.
    Ashwell JD, Lu FW, Vacchio MS. Glucocorticoids in T cell development and function. Annu Rev Immunol. 2000;18:309–45. Scholar
  106. 106.
    Lanza L, et al. Prednisone increases apoptosis in in vitro activated human peripheral blood T lymphocytes. Clin Exp Immunol. 1996;103:482–90.CrossRefGoogle Scholar
  107. 107.
    Mathian A, et al. Regulatory T cell responses to high-dose methylprednisolone in active systemic lupus erythematosus. PLoS One. 2015;10:e0143689. Scholar
  108. 108.
    Paliogianni F, Ahuja SS, Balow JP, Balow JE, Boumpas DT. Novel mechanism for inhibition of human T cells by glucocorticoids. Glucocorticoids inhibit signal transduction through IL-2 receptor. J Immunol. 1993;151:4081–9.PubMedGoogle Scholar
  109. 109.
    Wallen N, Kita H, Weiler D, Gleich GJ. Glucocorticoids inhibit cytokine-mediated eosinophil survival. J Immunol. 1991;147:3490–5.PubMedGoogle Scholar
  110. 110.
    Jegasothy BV, Ackerman CD, Todo S, Fung JJ, Abu-Elmagd K, Starzl TE. Tacrolimus (FK 506)–a new therapeutic agent for severe recalcitrant psoriasis. Arch Dermatol. 1992;128:781–5.CrossRefGoogle Scholar
  111. 111.
    Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Immunol Today. 1992;13:136–42. Scholar
  112. 112.
    Hirsch HH, et al. Polyomavirus BK replication in de novo kidney transplant patients receiving tacrolimus or cyclosporine: a prospective, randomized, multicenter study. Am J Transplant. 2013;13:136–45. Scholar
  113. 113.
    Kizilbash SJ, Rheault MN, Bangdiwala A, Matas A, Chinnakotla S, Chavers BM. Infection rates in tacrolimus versus cyclosporine-treated pediatric kidney transplant recipients on a rapid discontinuation of prednisone protocol: 1-year analysis. Pediatr Transplant. 2017;21:e12919. Scholar
  114. 114.
    Schwarz A, et al. Factors influencing viral clearing and renal function during polyomavirus BK-associated nephropathy after renal transplantation. Transplantation. 2012;94:396–402. Scholar
  115. 115.
    Ruggeri A, et al. Incidence and risk factors for hemorrhagic cystitis in unmanipulated haploidentical transplant recipients. Transpl Infect Dis. 2015;17: 822–30. Scholar
  116. 116.
    Rorije NM, et al. BK virus disease after allogeneic stem cell transplantation: a cohort analysis. Biol Blood Marrow Transplant. 2014;20:564–70. Scholar
  117. 117.
    Oz HS, Hughes WT. Novel anti-Pneumocystis carinii effects of the immunosuppressant mycophenolate mofetil in contrast to provocative effects of tacrolimus, sirolimus, and dexamethasone. J Infect Dis. 1997;175:901–4.CrossRefGoogle Scholar
  118. 118.
    Geissler EK. The influence of mTOR inhibitors on immunity and the relationship to post-transplant malignancy. Transplant Res. 2013;2:S2. Scholar
  119. 119.
    Rao RR, Li Q, Odunsi K, Shrikant PA. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity. 2010;32:67–78. Scholar
  120. 120.
    Brennan DC, et al. Effect of maintenance immunosuppressive drugs on virus pathobiology: evidence and potential mechanisms. Rev Med Virol. 2013;23: 97–125. Scholar
  121. 121.
    Cervera C, et al. Effect of mammalian target of rapamycin inhibitors on cytomegalovirus infection in kidney transplant recipients receiving polyclonal antilymphocyte globulins: a propensity score-matching analysis. Transpl Int. 2016;29:1216–25. Scholar
  122. 122.
    de Paula MI, et al. Long-term follow-up of de novo use of mTOR and Calcineurin inhibitors after kidney transplantation. Ther Drug Monit. 2016;38:22–31. Scholar
  123. 123.
    Hirsch HH, Yakhontova K, Lu M, Manzetti J. BK polyomavirus replication in renal tubular epithelial cells is inhibited by sirolimus, but activated by tacrolimus through a pathway involving FKBP-12. Am J Transplant. 2016;16:821–32. Scholar
  124. 124.
    Koo S, Marty FM, Baden LR. Infectious complications associated with immunomodulating biologic agents. Infect Dis Clin N Am. 2010;24:285–306. Scholar
  125. 125.
    Giles JT, Bathon JM. Serious infections associated with anticytokine therapies in the rheumatic diseases. J Intensive Care Med. 2004;19:320–34. Scholar
  126. 126.
    Ahn IE, Jerussi T, Farooqui M, Tian X, Wiestner A, Gea-Banacloche J. Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib. Blood. 2016;128: 1940–3. Scholar
  127. 127.
    Ghez D, et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood. 2018;131:1955–9. Scholar
  128. 128.
    Bercusson A, Colley T, Shah A, Warris A, Armstrong-James D. Ibrutinib blocks Btk-dependent NF-kB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis. Blood. 2018;132:1985. Scholar
  129. 129.
    Ullmann AJ, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356:335–47. Scholar
  130. 130.
    Tomblyn M, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15:1143–238. Scholar
  131. 131.
    Boeckh M, et al. Valganciclovir for the prevention of complications of late cytomegalovirus infection after allogeneic hematopoietic cell transplantation: a randomized trial. Ann Intern Med. 2015;162:1–10. Scholar
  132. 132.
    Saillard C, et al. Critically ill allogenic HSCT patients in the intensive care unit: a systematic review and meta-analysis of prognostic factors of mortality. Bone Marrow Transplant. 2018;53:1233. Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Division of Hematology and OncologyAras Medical CenterAnkaraTurkey

Personalised recommendations