Unique Complications and Limitations of Haploidentical Hematopoietic Cell Transplant

  • Hermann Einsele
  • Stephan Mielke
  • Matthias Hermann
Part of the Advances and Controversies in Hematopoietic Transplantation and Cell Therapy book series (ACHTCT)


Outcomes of haploidentical hematopoietic cell transplantation (haplo-HCT) have recently improved. In the past, limitations in expanding this form of transplant were related to profound in vivo and ex vivo T-cell depletion to avoid both primary graft rejection (PGF) and lethal graft-versus-host disease (GvHD). Consequently, T-lymphocyte reconstitution was markedly hindered leading to significant rates of lethal infections associated with high rates of non-relapse mortality (NRM) and relapse of the malignant disease, limiting this strategy only to patients with no suitable donor in place. Recent developments during the last 5 years have changed this scenario dramatically. Novel strategies allowing the add-back of manipulated and selected depletion of T-lymphocytes and post-transplant alloreactive T-cell depletion (TCD) by high-dose cyclophosphamide after unmanipulated bone marrow (BM) or peripheral blood (PB) hematopoietic cell transplantation reach out to almost similar outcomes known from transplants from HLA-matched related and HLA-matched unrelated donors.

Here, we summarize the unique complications of haplo-HCT related to the immunological consequences of crossing the major histocompatibility barrier and potent immunosuppression required during the process of transplantation, such as PGF, genomic loss of HLA-mismatched human leukocyte antigen and viral reactivation, and a consequence of delayed or incomplete immune reconstitution.


T-cell depletion Complications Haploidentical HLA Infections Viral Fungal Mortality Failure 


  1. 1.
    Kongtim P, Cao K, Ciurea SO. Donor specific anti-HLA antibody and risk of graft failure in haploidentical stem cell transplantation. Adv Hematol. 2016;2016:4025073.CrossRefGoogle Scholar
  2. 2.
    Ciceri F, Labopin M, Aversa F, Rowe JM, Bunjes D, Lewalle P, et al. A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood. 2008;112(9):3574–81.CrossRefGoogle Scholar
  3. 3.
    Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F, et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med. 1998;339(17):1186–93.CrossRefGoogle Scholar
  4. 4.
    Davies SM, Kollman C, Anasetti C, Antin JH, Gajewski J, Casper JT, et al. Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the national marrow donor program. Blood. 2000;96(13):4096–102.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Rubinstein P, Carrier C, Scaradavou A, Kurtzberg J, Adamson J, Migliaccio AR, et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med. 1998;339(22):1565–77.CrossRefGoogle Scholar
  6. 6.
    Doney K, Leisenring W, Storb R, Appelbaum FR. Primary treatment of acquired aplastic anemia: outcomes with bone marrow transplantation and immunosuppressive therapy. Seattle Bone Marrow Transplant Team. Ann Intern Med. 1997;126(2):107–15.CrossRefGoogle Scholar
  7. 7.
    Ross D, Jones M, Komanduri K, Levy RB. Antigen and lymphopenia-driven donor T cells are differentially diminished by post-transplantation administration of cyclophosphamide after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013;19(10):1430–8.CrossRefGoogle Scholar
  8. 8.
    Takanashi M, Fujiwara K, Tanaka H, Satake M, Nakajima K. The impact of HLA antibodies on engraftment of unrelated cord blood transplants. Transfusion. 2008;48(4):791–3.CrossRefGoogle Scholar
  9. 9.
    Ruggeri A, Rocha V, Masson E, Labopin M, Cunha R, Absi L, et al. Impact of donor-specific anti-HLA antibodies on graft failure and survival after reduced intensity conditioning-unrelated cord blood transplantation: a Eurocord, Societe Francophone d’Histocompatibilite et d’Immunogenetique (SFHI) and Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) analysis. Haematologica. 2013;98(7):1154–60.CrossRefGoogle Scholar
  10. 10.
    Ciurea SO, Thall PF, Wang X, Wang SA, Hu Y, Cano P, et al. Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation. Blood. 2011;118(22):5957–64.CrossRefGoogle Scholar
  11. 11.
    Patel R, Terasaki PI. Significance of the positive crossmatch test in kidney transplantation. N Engl J Med. 1969;280(14):735–9.CrossRefGoogle Scholar
  12. 12.
    Anasetti C, Amos D, Beatty PG, Appelbaum FR, Bensinger W, Buckner CD, et al. Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma. N Engl J Med. 1989;320(4):197–204.CrossRefGoogle Scholar
  13. 13.
    McKenna RM, Takemoto SK, Terasaki PI. Anti-HLA antibodies after solid organ transplantation. Transplantation. 2000;69(3):319–26.CrossRefGoogle Scholar
  14. 14.
    Everly MJ. Donor-specific anti-HLA antibody monitoring and removal in solid organ transplant recipients. Clin Transpl. 2011:319–25.Google Scholar
  15. 15.
    Ciurea SO, Thall PF, Milton DR, Barnes TH, Kongtim P, Carmazzi Y, et al. Complement-binding donor-specific anti-HLA antibodies and risk of primary graft failure in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21(8):1392–8.CrossRefGoogle Scholar
  16. 16.
    Xu H, Chilton PM, Tanner MK, Huang Y, Schanie CL, Dy-Liacco M, et al. Humoral immunity is the dominant barrier for allogeneic bone marrow engraftment in sensitized recipients. Blood. 2006;108(10):3611–9.CrossRefGoogle Scholar
  17. 17.
    Taylor PA, Ehrhardt MJ, Roforth MM, Swedin JM, Panoskaltsis-Mortari A, Serody JS, et al. Preformed antibody, not primed T cells, is the initial and major barrier to bone marrow engraftment in allosensitized recipients. Blood. 2007;109(3):1307–15.CrossRefGoogle Scholar
  18. 18.
    Botto M, Walport MJ. C1q, autoimmunity and apoptosis. Immunobiology. 2002;205(4–5):395–406.CrossRefGoogle Scholar
  19. 19.
    Chen G, Sequeira F, Tyan DB. Novel C1q assay reveals a clinically relevant subset of human leukocyte antigen antibodies independent of immunoglobulin G strength on single antigen beads. Hum Immunol. 2011;72(10):849–58.CrossRefGoogle Scholar
  20. 20.
    Sacks SH, Zhou W. The role of complement in the early immune response to transplantation. Nat Rev Immunol. 2012;12(6):431–42.CrossRefGoogle Scholar
  21. 21.
    Suciu-Foca N, Reed E, Marboe C, Harris P, PX Y, Sun YK, et al. The role of anti-HLA antibodies in heart transplantation. Transplantation. 1991;51(3):716–24.CrossRefGoogle Scholar
  22. 22.
    Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transplant. 2004;4(3):438–43.CrossRefGoogle Scholar
  23. 23.
    Mao Q, Terasaki PI, Cai J, Briley K, Catrou P, Haisch C, et al. Extremely high association between appearance of HLA antibodies and failure of kidney grafts in a five-year longitudinal study. Am J Transplant. 2007;7(4):864–71.CrossRefGoogle Scholar
  24. 24.
    Ting A, Hasegawa T, Ferrone S, Reisfeld RA. Presensitization detected by sensitive crossmatch tests. Transplant Proc. 1973;5(1):813–7.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Zachary AA, Klingman L, Thorne N, Smerglia AR, Teresi GA. Variations of the lymphocytotoxicity test. An evaluation of sensitivity and specificity. Transplantation. 1995;60(5):498–503.CrossRefGoogle Scholar
  26. 26.
    Ottinger HD, Rebmann V, Pfeiffer KA, Beelen DW, Kremens B, Runde V, et al. Positive serum crossmatch as predictor for graft failure in HLA-mismatched allogeneic blood stem cell transplantation. Transplantation. 2002;73(8):1280–5.CrossRefGoogle Scholar
  27. 27.
    Marfo K, Lu A, Ling M, Akalin E. Desensitization protocols and their outcome. Clin J Am Soc Nephrol. 2011;6(4):922–36.CrossRefGoogle Scholar
  28. 28.
    Ratkovec RM, Hammond EH, O’Connell JB, Bristow MR, DeWitt CW, Richenbacher WE, et al. Outcome of cardiac transplant recipients with a positive donor-specific crossmatch—preliminary results with plasmapheresis. Transplantation. 1992;54(4):651–5.CrossRefGoogle Scholar
  29. 29.
    Pisani BA, Mullen GM, Malinowska K, Lawless CE, Mendez J, Silver MA, et al. Plasmapheresis with intravenous immunoglobulin G is effective in patients with elevated panel reactive antibody prior to cardiac transplantation. J Heart Lung Transplant. 1999;18(7):701–6.CrossRefGoogle Scholar
  30. 30.
    Grauhan O, Knosalla C, Ewert R, Hummel M, Loebe M, Weng YG, et al. Plasmapheresis and cyclophosphamide in the treatment of humoral rejection after heart transplantation. J Heart Lung Transplant. 2001;20(3):316–21.CrossRefGoogle Scholar
  31. 31.
    Baran DA, Lubitz S, Alvi S, Fallon JT, Kaplan S, Galin I, et al. Refractory humoral cardiac allograft rejection successfully treated with a single dose of rituximab. Transplant Proc. 2004;36(10):3164–6.CrossRefGoogle Scholar
  32. 32.
    Maruta A, Fukawa H, Kanamori H, Harano H, Noguchi T, Kodama F, et al. Donor-HLA-incompatible marrow transplantation with an anti-donor cytotoxic antibody in the serum of the patient. Bone Marrow Transplant. 1991;7(5):397–400.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Ciurea SO, de Lima M, Cano P, Korbling M, Giralt S, Shpall EJ, et al. High risk of graft failure in patients with anti-HLA antibodies undergoing haploidentical stem-cell transplantation. Transplantation. 2009;88(8):1019–24.CrossRefGoogle Scholar
  34. 34.
    Yoshihara S, Maruya E, Taniguchi K, Kaida K, Kato R, Inoue T, et al. Risk and prevention of graft failure in patients with preexisting donor-specific HLA antibodies undergoing unmanipulated haploidentical SCT. Bone Marrow Transplant. 2012;47(4):508–15.CrossRefGoogle Scholar
  35. 35.
    Fasano RM, Mamcarz E, Adams S, Donohue Jerussi T, Sugimoto K, Tian X, et al. Persistence of recipient human leucocyte antigen (HLA) antibodies and production of donor HLA antibodies following reduced intensity allogeneic haematopoietic stem cell transplantation. Br J Haematol. 2014;166(3):425–34.CrossRefGoogle Scholar
  36. 36.
    Leffell MS, Jones RJ, Gladstone DE. Donor HLA-specific Abs: to BMT or not to BMT? Bone Marrow Transplant. 2015;50(6):751–8.CrossRefGoogle Scholar
  37. 37.
    Suchin EJ, Langmuir PB, Palmer E, Sayegh MH, Wells AD, Turka LA. Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J Immunol. 2001;166(2):973–81.CrossRefGoogle Scholar
  38. 38.
    Koopman LA, Corver WE, van der Slik AR, Giphart MJ, Fleuren GJ. Multiple genetic alterations cause frequent and heterogeneous human histocompatibility leukocyte antigen class I loss in cervical cancer. J Exp Med. 2000;191(6):961–76.CrossRefGoogle Scholar
  39. 39.
    Cabrera T, Maleno I, Lopez-Nevot MA, Redondo M, Fernandez MA, Collado A, et al. High frequency of HLA-B44 allelic losses in human solid tumors. Hum Immunol. 2003;64(10):941–50.CrossRefGoogle Scholar
  40. 40.
    Vago L, Toffalori C, Ciceri F, Fleischhauer K. Genomic loss of mismatched human leukocyte antigen and leukemia immune escape from haploidentical graft-versus-leukemia. Semin Oncol. 2012;39(6):707–15.CrossRefGoogle Scholar
  41. 41.
    Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Stanghellini MT, et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med. 2009;361(5):478–88.CrossRefGoogle Scholar
  42. 42.
    Villalobos IB, Takahashi Y, Akatsuka Y, Muramatsu H, Nishio N, Hama A, et al. Relapse of leukemia with loss of mismatched HLA resulting from uniparental disomy after haploidentical hematopoietic stem cell transplantation. Blood. 2010;115(15):3158–61.CrossRefGoogle Scholar
  43. 43.
    McCurdy SR, Iglehart BS, Batista DA, Gocke CD, Ning Y, Knaus HA, et al. Loss of the mismatched human leukocyte antigen haplotype in two acute myelogenous leukemia relapses after haploidentical bone marrow transplantation with post-transplantation cyclophosphamide. Leukemia. 2016;30(10):2102–6.CrossRefGoogle Scholar
  44. 44.
    Tamaki H, Fujioka T, Ikegame K, Yoshihara S, Kaida K, Taniguchi K, et al. Different mechanisms causing loss of mismatched human leukocyte antigens in relapsing t(6;11)(q27;q23) acute myeloid leukemia after haploidentical transplantation. Eur J Haematol. 2012;89(6):497–500.CrossRefGoogle Scholar
  45. 45.
    Crucitti L, Crocchiolo R, Toffalori C, Mazzi B, Greco R, Signori A, et al. Incidence, risk factors and clinical outcome of leukemia relapses with loss of the mismatched HLA after partially incompatible hematopoietic stem cell transplantation. Leukemia. 2015;29(5):1143–52.CrossRefGoogle Scholar
  46. 46.
    Barrett J, Blazar BR. Genetic trickery—escape of leukemia from immune attack. N Engl J Med. 2009;361(5):524–5.CrossRefGoogle Scholar
  47. 47.
    Federmann B, Hagele M, Pfeiffer M, Wirths S, Schumm M, Faul C, et al. Immune reconstitution after haploidentical hematopoietic cell transplantation: impact of reduced intensity conditioning and CD3/CD19 depleted grafts. Leukemia. 2011;25(1):121–9.CrossRefGoogle Scholar
  48. 48.
    Handgretinger R, Chen X, Pfeiffer M, Mueller I, Feuchtinger T, Hale GA, et al. Feasibility and outcome of reduced-intensity conditioning in haploidentical transplantation. Ann N Y Acad Sci. 2007;1106:279–89.CrossRefGoogle Scholar
  49. 49.
    Dufort G, Pisano S, Incoronato A, Castiglioni M, Carracedo M, Pages C, et al. Feasibility and outcome of haploidentical SCT in pediatric high-risk hematologic malignancies and Fanconi anemia in Uruguay. Bone Marrow Transplant. 2012;47(5):663–8.CrossRefGoogle Scholar
  50. 50.
    Rizzieri DA, Koh LP, Long GD, Gasparetto C, Sullivan KM, Horwitz M, et al. Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution. J Clin Oncol. 2007;25(6):690–7.CrossRefGoogle Scholar
  51. 51.
    Oevermann L, Lang P, Feuchtinger T, Schumm M, Teltschik HM, Schlegel P, et al. Immune reconstitution and strategies for rebuilding the immune system after haploidentical stem cell transplantation. Ann N Y Acad Sci. 2012;1266:161–70.CrossRefGoogle Scholar
  52. 52.
    Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641–50.CrossRefGoogle Scholar
  53. 53.
    Ciurea SO, Mulanovich V, Saliba RM, Bayraktar UD, Jiang Y, Bassett R, et al. Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18(12):1835–44.CrossRefGoogle Scholar
  54. 54.
    Tischer J, Engel N, Fritsch S, Prevalsek D, Hubmann M, Schulz C, et al. Virus infection in HLA-haploidentical hematopoietic stem cell transplantation: incidence in the context of immune recovery in two different transplantation settings. Ann Hematol. 2015;94(10):1677–88.CrossRefGoogle Scholar
  55. 55.
    Lowdell MW, Craston R, Ray N, Koh M, Galatowicz G, Prentice HG. The effect of T cell depletion with Campath-1M on immune reconstitution after chemotherapy and allogeneic bone marrow transplant as treatment for leukaemia. Bone Marrow Transplant. 1998;21(7):679–86.CrossRefGoogle Scholar
  56. 56.
    Boeckh M, Leisenring W, Riddell SR, Bowden RA, Huang ML, Myerson D, et al. Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood. 2003;101(2):407–14.CrossRefGoogle Scholar
  57. 57.
    Almyroudis NG, Jakubowski A, Jaffe D, Sepkowitz K, Pamer E, O’Reilly RJ, et al. Predictors for persistent cytomegalovirus reactivation after T-cell-depleted allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2007;9(4):286–94.CrossRefGoogle Scholar
  58. 58.
    Reshma Ramlal KS, Cerrada SL, Srour SA, Julianne Chen R, Rondon G, Rezvani K, Oran B, Olson A, Shpall EJ, Champlin RE, Ciurea SO. Viral reactivation in haploidentical transplants using post-transplantation cyclophosphamide a single institution experience. Biol Blood Marrow Transplant. 2016;22:S19–S481. AbstractGoogle Scholar
  59. 59.
    Goldsmith SR, Slade M, DiPersio JF, Westervelt P, Lawrence SJ, Uy GL, et al. Cytomegalovirus viremia, disease, and impact on relapse in T-cell replete peripheral blood haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide. Haematologica. 2016;101(11):e465–e8.CrossRefGoogle Scholar
  60. 60.
    van Burik JA, Carter SL, Freifeld AG, High KP, Godder KT, Papanicolaou GA, et al. Higher risk of cytomegalovirus and aspergillus infections in recipients of T cell-depleted unrelated bone marrow: analysis of infectious complications in patients treated with T cell depletion versus immunosuppressive therapy to prevent graft-versus-host disease. Biol Blood Marrow Transplant. 2007;13(12):1487–98.CrossRefGoogle Scholar
  61. 61.
    Mulanovich VE, Jiang Y, de Lima M, Shpall EJ, Champlin RE, Ciurea SO. Infectious complications in cord blood and T-cell depleted haploidentical stem cell transplantation. Am J Blood Res. 2011;1(1):98–105.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Nichols WG, Corey L, Gooley T, Davis C, Boeckh M. High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)—seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection. J Infect Dis. 2002;185(3):273–82.CrossRefGoogle Scholar
  63. 63.
    Preiser W, Brauninger S, Schwerdtfeger R, Ayliffe U, Garson JA, Brink NS, et al. Evaluation of diagnostic methods for the detection of cytomegalovirus in recipients of allogeneic stem cell transplants. J Clin Virol. 2001;20(1-2):59–70.CrossRefGoogle Scholar
  64. 64.
    Reusser P, Einsele H, Lee J, Volin L, Rovira M, Engelhard D, et al. Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation. Blood. 2002;99(4):1159–64.CrossRefGoogle Scholar
  65. 65.
    Cesaro S, Zhou X, Manzardo C, Buonfrate D, Cusinato R, Tridello G, et al. Cidofovir for cytomegalovirus reactivation in pediatric patients after hematopoietic stem cell transplantation. J Clin Virol. 2005;34(2):129–32.CrossRefGoogle Scholar
  66. 66.
    Chesters PM, Heritage J, McCance DJ. Persistence of DNA sequences of BK virus and JC virus in normal human tissues and in diseased tissues. J Infect Dis. 1983;147(4):676–84.CrossRefGoogle Scholar
  67. 67.
    Bedi A, Miller CB, Hanson JL, Goodman S, Ambinder RF, Charache P, et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol. 1995;13(5):1103–9.CrossRefGoogle Scholar
  68. 68.
    Azzi A, Cesaro S, Laszlo D, Zakrzewska K, Ciappi S, De Santis R, et al. Human polyomavirus BK (BKV) load and haemorrhagic cystitis in bone marrow transplantation patients. J Clin Virol. 1999;14(2):79–86.CrossRefGoogle Scholar
  69. 69.
    Rorije NM, Shea MM, Satyanarayana G, Hammond SP, Ho VT, Baden LR, et al. BK virus disease after allogeneic stem cell transplantation: a cohort analysis. Biol Blood Marrow Transplant. 2014;20(4):564–70.CrossRefGoogle Scholar
  70. 70.
    Li R, Sharma BN, Linder S, Gutteberg TJ, Hirsch HH, Rinaldo CH. Characteristics of polyomavirus BK (BKPyV) infection in primary human urothelial cells. Virology. 2013;440(1):41–50.CrossRefGoogle Scholar
  71. 71.
    Ruggeri A, Roth-Guepin G, Battipaglia G, Mamez AC, Malard F, Gomez A, et al. Incidence and risk factors for hemorrhagic cystitis in unmanipulated haploidentical transplant recipients. Transpl Infect Dis. 2015;17(6):822–30.CrossRefGoogle Scholar
  72. 72.
    Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, et al. Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: results of a prospective phase II trial. Biol Blood Marrow Transplant. 2012;18(12):1859–66.CrossRefGoogle Scholar
  73. 73.
    Raiola AM, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, et al. Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning. Biol Blood Marrow Transplant. 2013;19(1):117–22.CrossRefGoogle Scholar
  74. 74.
    Fogazzi GB, Cantu M, Saglimbeni L. ‘Decoy cells’ in the urine due to polyomavirus BK infection: easily seen by phase-contrast microscopy. Nephrol Dial Transplant. 2001;16(7):1496–8.CrossRefGoogle Scholar
  75. 75.
    Held TK, Biel SS, Nitsche A, Kurth A, Chen S, Gelderblom HR, et al. Treatment of BK virus-associated hemorrhagic cystitis and simultaneous CMV reactivation with cidofovir. Bone Marrow Transplant. 2000;26(3):347–50.CrossRefGoogle Scholar
  76. 76.
    Savona MR, Newton D, Frame D, Levine JE, Mineishi S, Kaul DR. Low-dose cidofovir treatment of BK virus-associated hemorrhagic cystitis in recipients of hematopoietic stem cell transplant. Bone Marrow Transplant. 2007;39(12):783–7.CrossRefGoogle Scholar
  77. 77.
    Gorczynska E, Turkiewicz D, Rybka K, Toporski J, Kalwak K, Dyla A, et al. Incidence, clinical outcome, and management of virus-induced hemorrhagic cystitis in children and adolescents after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2005;11(10):797–804.CrossRefGoogle Scholar
  78. 78.
    Heemskerk B, Lankester AC, van Vreeswijk T, Beersma MF, Claas EC, Veltrop-Duits LA, et al. Immune reconstitution and clearance of human adenovirus viremia in pediatric stem-cell recipients. J Infect Dis. 2005;191(4):520–30.CrossRefGoogle Scholar
  79. 79.
    Flomenberg P, Babbitt J, Drobyski WR, Ash RC, Carrigan DR, Sedmak GV, et al. Increasing incidence of adenovirus disease in bone marrow transplant recipients. J Infect Dis. 1994;169(4):775–81.CrossRefGoogle Scholar
  80. 80.
    Leruez-Ville M, Minard V, Lacaille F, Buzyn A, Abachin E, Blanche S, et al. Real-time blood plasma polymerase chain reaction for management of disseminated adenovirus infection. Clin Infect Dis. 2004;38(1):45–52.CrossRefGoogle Scholar
  81. 81.
    Echavarria M, Forman M, van Tol MJ, Vossen JM, Charache P, Kroes AC. Prediction of severe disseminated adenovirus infection by serum PCR. Lancet. 2001;358(9279):384–5.CrossRefGoogle Scholar
  82. 82.
    Lion T, Baumgartinger R, Watzinger F, Matthes-Martin S, Suda M, Preuner S, et al. Molecular monitoring of adenovirus in peripheral blood after allogeneic bone marrow transplantation permits early diagnosis of disseminated disease. Blood. 2003;102(3):1114–20.CrossRefGoogle Scholar
  83. 83.
    Howard DS, Phillips IG, Reece DE, Munn RK, Henslee-Downey J, Pittard M, et al. Adenovirus infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 1999;29(6):1494–501.CrossRefGoogle Scholar
  84. 84.
    Taniguchi K, Yoshihara S, Tamaki H, Fujimoto T, Ikegame K, Kaida K, et al. Incidence and treatment strategy for disseminated adenovirus disease after haploidentical stem cell transplantation. Ann Hematol. 2012;91(8):1305–12.CrossRefGoogle Scholar
  85. 85.
    de Pagter AP, Haveman LM, Schuurman R, Schutten M, Bierings M, Boelens JJ. Adenovirus DNA positivity in nasopharyngeal aspirate preceding hematopoietic stem cell transplantation: a very strong risk factor for adenovirus DNAemia in pediatric patients. Clin Infect Dis. 2009;49(10):1536–9.CrossRefGoogle Scholar
  86. 86.
    Versluys AB, Rossen JW, van Ewijk B, Schuurman R, Bierings MB, Boelens JJ. Strong association between respiratory viral infection early after hematopoietic stem cell transplantation and the development of life-threatening acute and chronic alloimmune lung syndromes. Biol Blood Marrow Transplant. 2010;16(6):782–91.CrossRefGoogle Scholar
  87. 87.
    Myers GD, Krance RA, Weiss H, Kuehnle I, Demmler G, Heslop HE, et al. Adenovirus infection rates in pediatric recipients of alternate donor allogeneic bone marrow transplants receiving either antithymocyte globulin (ATG) or alemtuzumab (Campath). Bone Marrow Transplant. 2005;36(11):1001–8.CrossRefGoogle Scholar
  88. 88.
    Robin M, Marque-Juillet S, Scieux C, Peffault de Latour R, Ferry C, Rocha V, et al. Disseminated adenovirus infections after allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcome. Haematologica. 2007;92(9):1254–7.CrossRefGoogle Scholar
  89. 89.
    Kampmann B, Cubitt D, Walls T, Naik P, Depala M, Samarasinghe S, et al. Improved outcome for children with disseminated adenoviral infection following allogeneic stem cell transplantation. Br J Haematol. 2005;130(4):595–603.CrossRefGoogle Scholar
  90. 90.
    Kuypers J, Wright N, Ferrenberg J, Huang ML, Cent A, Corey L, et al. Comparison of real-time PCR assays with fluorescent-antibody assays for diagnosis of respiratory virus infections in children. J Clin Microbiol. 2006;44(7):2382–8.CrossRefGoogle Scholar
  91. 91.
    Gustafson I, Lindblom A, Yun Z, Omar H, Engstrom L, Lewensohn-Fuchs I, et al. Quantification of adenovirus DNA in unrelated donor hematopoietic stem cell transplant recipients. J Clin Virol. 2008;43(1):79–85.CrossRefGoogle Scholar
  92. 92.
    Omar H, Yun Z, Lewensohn-Fuchs I, Perez-Bercoff L, Orvell C, Engstrom L, et al. Poor outcome of adenovirus infections in adult hematopoietic stem cell transplant patients with sustained adenovirus viremia. Transpl Infect Dis. 2010;12(5):465–9.CrossRefGoogle Scholar
  93. 93.
    Symeonidis N, Jakubowski A, Pierre-Louis S, Jaffe D, Pamer E, Sepkowitz K, et al. Invasive adenoviral infections in T-cell-depleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of cidofovir. Transpl Infect Dis. 2007;9(2):108–13.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Hermann Einsele
    • 1
  • Stephan Mielke
    • 1
  • Matthias Hermann
    • 1
  1. 1.Department of Internal Medicine IIUniversity of WuerzburgWuerzburgGermany

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