Abstract
Adenovirus (adv) is a significant cause of morbidity and mortality in pediatric hematopoietic stem cell transplant recipients, and control of infection seems to require antigen-specific T cells. We evaluated the recovery of adv-specific cellular immunity in this patient population related to degree of T-cell immunosuppressive therapy and compared this to adv cellular immunity of normal donors. Over 12 months, we monitored for adv DNA in stool and blood of patients and in the blood of a normal donor group. Twenty-two pediatric hematopoietic stem cell transplant (HSCT) patients (14 months–20 years) who received matched-related (MRD n=6), mismatched related (Haplo n=6) or matched unrelated donor (MUD n=10) grafts, were followed and results compared to healthy controls (n=8). Adv was detected by polymerase chain reaction in blood and/or stool from 81.8% of patients on at least one occasion post-HSCT, but only 68% of patients developed symptomatic adv infections. Recovery of adv-specific T cells was significantly delayed in the MUD and Haplo recipients, whereas recovery in the MRD group was similar to levels detected in healthy donors within 30 days post-transplant. In conclusion, recipients of alternative donor transplants at our institution have significantly delayed adv-specific cellular immune recovery, which correlates to an increased risk of adv-associated morbidity and mortality.
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References
Horwitz MS . Adenoviruses Fields Virology. Lippincott, Williams & Wilkins: Philadelphia, PA, USA, 2002.
Hale GA, Heslop HE, Krance RA, Brenner MK, Jayawardene D, Srivastava DK et al. Adenovirus infection after pediatric bone marrow transplantation. Bone Marrow Transplant 1999; 23: 277–282.
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: 775–781.
Blanke C, Clark C, Broun ER, Tricot G, Cunningham I, Cornetta K et al. Evolving pathogens in allogeneic bone marrow transplantation: increased fatal adenoviral infections. Am J Med 1995; 99: 326–328.
Baldwin A, Kingman H, Darville M, Foot AB, Grier D, Cornish JM et al. Outcome and clinical course of 100 patients with adenovirus infection following bone marrow transplantation. Bone Marrow Transplant 2000; 26: 1333–1338.
de Mezerville MH, Tellier R, Richardson S, Hebert D, Doyle J, Allen U . Adenoviral infections in pediatric transplant recipients: a hospital-based study. Pediatric Infect Dis J 2006; 25: 815–818.
Walls T, Hawrami K, Ushiro-Lumb I, Shingadia D, Saha V, Shankar AG . Adenovirus infection after pediatric bone marrow transplantation: is treatment always necessary? Clin Infect Dis 2005; 40: 1244–1249.
Howard DS, Phillips II GL, Reece DE, Munn RK, Henslee-Downey J, Pittard M et al. Adenovirus infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 1999; 29: 1494–1501.
Runde V, Ross S, Trenschel R, Lagemann E, Basu O, Renzing-Kohler K et al. Adenoviral infection after allogeneic stem cell transplantation (SCT): report on 130 patients from a single SCT unit involved iin a prospective multi center surveillance study. Bone Marrow Transplant 2001; 28: 51–57.
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: 520–530.
Chakrabarti S, Mautner V, Osman H, Collingham KE, Fegan CD, Klapper PE et al. Adenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery. Blood 2002; 100: 1619–1627.
Feuchtinger T, Lucke J, Hamprecht K, Richard C, Handgretinger R, Schumm M et al. Detection of adenovirus-specific T cells in children with adenovirus infection after allogeneic stem cell transplantation. Br J Haematol 2005; 128: 503–509.
Feuchtinger T, Richard C, Pfeiffer M, Neuhauser F, Lucke J, Handgretinger R et al. Adenoviral infections after transplantation of positive selected stem cells from haploidentical donors in children: an update. Clin Padiatrics 2006; 217: 339–344.
Leen AM, Myers GD, Bollard CM, Huls MH, Sili U, Gee AP et al. T-cell immunotherapy for adenoviral infections of stem-cell transplant recipients. Ann NY Acad Sci 2006; 1062: 104–115.
Ljungman P, Ribaud P, Eyrich M, Matthes-Martin S, Einsele H, Bleakley M et al. Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2003; 31: 481–486.
Yusuf U, Hale GA, Carr J, Gu Z, Benaim E, Woodard P et al. Cidofovir for the treatment of adenoviral infection in pediatric hematopoietic stem cell transplant patients. Transplantation 2006; 81: 1398–1404.
Popat U, Heslop HE, Durett A, May R, Krance RA, Brenner MK et al. Outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation (RISCT) using antilymphocyte antibodies in patients with high-risk acute myeloid leukemia (AML). Bone Marrow Transplant 2006; 37: 547–552.
Hongeng S, Krance RA, Bowman LC, Srivastava DK, Cunningham JM, Horwitz EM et al. Outcomes of transplantation with matched-sibling and unrelated-donor bone marrow in children with leukaemia. Lancet 2006; 350: 767–771.
Heim A, Ebnet C, Harste G, Pring-Akerblom P . Rapid and quantitative detection of human adenovirus DNA by real-time PCR. J Med Virol 2003; 70: 228–239.
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: 1114–1120.
Leen AM, Sili U, Vanin EF, Jewell AM, Xie W, Vignali D et al. Conserved CTL epitopes on the adenovirus hexon protein expand subgroup cross-reactive and subgroup-specific CD8+ T cells. Blood 2004; 104: 2432–2440.
Kalbfleisch JD, Prentice RL . The Statistical Analysis of Failure Time Data. John-Wiley: Hoboken, NJ, USA, 1980.
Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Statist 1988; 16: 1141–1154.
Gray B . cmprsk: Subdistribution Analysis of Competing Risks 2004. R package version 2.2.1. http://www.r-project.org, http://biowww.dfci.harvard.edu/~gray.
Avivi I, Chakrabarti S, Milligan DW, Waldmann H, Hale GA, Osman H et al. Incidence and outcome of adenovirus disease in transplant recipients after reduced-intensity conditioning with alemtuzumab. Biol Blood Marrow Transplant 2004; 10: 186–194.
Lenaerts L, Naesens L . Antiviral therapy for adenovirus infections. Antiviral Res 2006; 71: 172–180.
Hoffman JA, Shah AJ, Ross LA, Kapoor N . Adenoviral infections and a prospective trial of cidofovir in pediatric hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006; 7: 388–394.
Seidemann K, Heim A, Pfister ED, Koditz H, Beilken A, Sander A et al. Monitoring of adenovirus infection in pediatric transplant recipients by quantitative PCR: report of six cases and review of the literature. Am J Transplant 2004; 4: 2102–2108.
Feuchtinger T, Lang P, Hamprecht K, Schumm M, Greil J, Jahn G et al. Isolation and expansion of human adenovirus-specific CD4+ and CD8+ T cells according to IFN-gamma secretion for adjuvant immunotherapy. Exp Hematol 2004; 32: 282–289.
Feuchtinger T, Matthes-Martin S, Richard C, Lion T, Fuhrer M, Hamprecht K et al. Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Br J Haematol 2006; 134: 64–76.
Regn S, Raffegerst S, Chen X, Schendel D, Kolb HJ, Roskrow M . Ex vivo generation of cytotoxic T lymphocytes specific for one or two distinct viruses for the prophylaxis of patients receiving an allogeneic bone marrow transplant. Bone Marrow Transplant 2001; 27: 53–64.
Leen AM, Myers GD, Sili U, Huls MH, Weiss H, Leung KS et al. Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals. Nat Med 2006; 12: 1160–1166.
Leen AM, Sili U, Savoldo B, Jewell AM, Piedra PA, Brenner MK et al. Fiber-modified adenoviruses generate subgroup cross-reactive, adenovirus-specific cytotoxic T lymphocytes for therapeutic applications. Blood 2004; 103: 1011–1019.
Amrolia PJ, Muccioli-Casadei G, Huls MH, Adams S, Durrett A, Gee A et al. Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplant. Blood 2006; 108: 1797–1808.
Acknowledgements
This work was supported in part by a NRSA Viral Oncology Training Grant to GDM, a Doris Duke Distinguished Clinical Scientist Award to HEH and an Amy Strelzer Manasevit Scholar award from the NMDP to CMB.
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Myers, G., Bollard, C., Wu, MF. et al. Reconstitution of adenovirus-specific cell-mediated immunity in pediatric patients after hematopoietic stem cell transplantation. Bone Marrow Transplant 39, 677–686 (2007). https://doi.org/10.1038/sj.bmt.1705645
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DOI: https://doi.org/10.1038/sj.bmt.1705645
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