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Age matters: older age as a risk factor for CMV reactivation in the CMV serostatus–positive kidney transplant recipient

European Journal of Clinical Microbiology & Infectious Diseases volume 39, pages 455–463 (2020)Cite this article

Abstract

Evaluate risk factors for cytomegalovirus (CMV) reactivation during the first year after kidney transplantation in the CMV-seropositive older recipient. Retrospective single-center study. Between 2011 and 2015, 91 patients ≥ 65 years received a kidney transplant; these were matched with 91 controls, aged 40–60. Risk of CMV reactivation in the CMV-seropositive recipients was analyzed. Sixty-three older and 54 younger recipients were included; 50% had received CMV-directed prophylaxis. CMV reactivation was significantly more frequent in the older group (71.4% vs 44.4%, p = 0.003) and occurred earlier (p = 0.003). A multivariate model showed that only age was associated with CMV reactivation (OR 2.48, p = 0.03). After excluding patients that received thymoglobulin, older age group remained the only risk factor of CMV reactivation (OR 3.81, p = 0.014). Recurrent event analysis showed that the older cohort had an HR of 1.94 (p = 0.01) of CMV viremia; there was significant episode-cohort interaction (p < 0.01). While the older group had a higher risk of infection (HR = 2.43), after the initial episode the relative hazards were approximately equal (HR = 1.08, at period 2). This suggests that it is key to specifically avoid the first episode of reactivation. Universal prophylaxis or a hybrid prophylaxis model should be considered in the CMV-seropositive kidney transplant recipient aged ≥ 65 years.

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References

  1. Yoshikawa TT, Norman DC (2017) Geriatric infectious diseases: current concepts on diagnosis and management. J Am Geriatr Soc 65(3):631–641. https://doi.org/10.1111/jgs.14731

    Article  PubMed  Google Scholar 

  2. Mouton CP, Bazaldua OV, Pierce B, Espino DV (2001) Common infections in older adults. Am Fam Physician 63(2):257–268

    CAS  PubMed  Google Scholar 

  3. Meier-Kriesche HU, Ojo AO, Hanson JA, Kaplan B (2001) Exponentially increased risk of infectious death in older renal transplant recipients. Kidney Int 59(4):1539–1543. https://doi.org/10.1046/j.1523-1755.2001.0590041539.x

    CAS  Article  PubMed  Google Scholar 

  4. Huang E, Segev DL, Rabb H (2009) Kidney transplantation in the elderly. Semin Nephrol 29(6):621–635. https://doi.org/10.1016/j.semnephrol.2009.07.011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Trouillhet I, Benito N, Cervera C, Rivas P, Cofan F, Almela M, Angeles Marcos M, Puig de la Bellacasa J, Pumarola T, Oppenheimer F, Moreno-Camacho A (2005) Influence of age in renal transplant infections: cases and controls study. Transplantation 80(7):989–992

    Article  Google Scholar 

  6. Adani GL, Baccarani U, Crestale S, Pravisani R, Isola M, Tulissi P, Vallone C, Nappi R, Risaliti A (2019) Kidney transplantation in elderly recipients: a single-center experience. Transplant Proc 51(1):132–135. https://doi.org/10.1016/j.transproceed.2018.04.081

    CAS  Article  PubMed  Google Scholar 

  7. Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A (2018) The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation 102(6):900–931. https://doi.org/10.1097/tp.0000000000002191

    Article  PubMed  Google Scholar 

  8. Opelz G, Dohler B, Ruhenstroth A (2004) Cytomegalovirus prophylaxis and graft outcome in solid organ transplantation: a collaborative transplant study report. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 4(6):928–936. https://doi.org/10.1111/j.1600-6143.2004.00451.x

    Article  Google Scholar 

  9. Bate SL, Dollard SC, Cannon MJ (2010) Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004. Clin Infect Dis 50(11):1439–1447. https://doi.org/10.1086/652438

    Article  PubMed  Google Scholar 

  10. van Boven M, van de Kassteele J, Korndewal MJ, van Dorp CH, Kretzschmar M, van der Klis F, de Melker HE, Vossen AC, van Baarle D (2017) Infectious reactivation of cytomegalovirus explaining age- and sex-specific patterns of seroprevalence. PLoS Comput Biol 13(9):e1005719. https://doi.org/10.1371/journal.pcbi.1005719

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Kliem V, Fricke L, Wollbrink T, Burg M, Radermacher J, Rohde F (2008) Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized clinical trial. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 8(5):975–983. https://doi.org/10.1111/j.1600-6143.2007.02133.x

    CAS  Article  Google Scholar 

  12. Witzke O, Hauser IA, Bartels M, Wolf G, Wolters H, Nitschke M (2012) Valganciclovir prophylaxis versus preemptive therapy in cytomegalovirus-positive renal allograft recipients: 1-year results of a randomized clinical trial. Transplantation 93(1):61–68. https://doi.org/10.1097/TP.0b013e318238dab3

    CAS  Article  PubMed  Google Scholar 

  13. Khoury JA, Storch GA, Bohl DL, Schuessler RM, Torrence SM, Lockwood M, Gaudreault-Keener M, Koch MJ, Miller BW, Hardinger KL, Schnitzler MA, Brennan DC (2006) Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 6(9):2134–2143. https://doi.org/10.1111/j.1600-6143.2006.01413.x

    CAS  Article  Google Scholar 

  14. Reischig T, Jindra P, Hes O, Svecova M, Klaboch J, Treska V (2008) Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 8(1):69–77. https://doi.org/10.1111/j.1600-6143.2007.02031.x

    CAS  Article  Google Scholar 

  15. Spinner ML, Saab G, Casabar E, Bowman LJ, Storch GA, Brennan DC (2010) Impact of prophylactic versus preemptive valganciclovir on long-term renal allograft outcomes. Transplantation 90(4):412–418. https://doi.org/10.1097/TP.0b013e3181e81afc

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Luna E, Caravaca F, Ferreira F, Fernandez N, Martin P, Vargas ML, Saenz de Santamaria J, Garcia Pino G, Azevedo L, Munoz Sanz A (2016) Effect of cytomegalovirus infection on survival of older kidney transplant patients (D+/R+): impact of valganciclovir prophylaxis versus preemptive therapy. Transplant Proc 48(9):2931–2937. https://doi.org/10.1016/j.transproceed.2016.06.062

    CAS  Article  PubMed  Google Scholar 

  17. Witzke O, Nitschke M, Bartels M, Wolters H, Wolf G, Reinke P, Hauser IA, Alshuth U, Kliem V (2018) Valganciclovir prophylaxis versus preemptive therapy in cytomegalovirus-positive renal allograft recipients: long-term results after 7 years of a randomized clinical trial. Transplantation 102(5):876–882. https://doi.org/10.1097/tp.0000000000002024

    CAS  Article  PubMed  Google Scholar 

  18. Hibberd PL, Tolkoff-Rubin NE, Conti D, Stuart F, Thistlethwaite JR, Neylan JF, Snydman DR, Freeman R, Lorber MI, Rubin RH (1995) Preemptive ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recipients. A randomized controlled trial. Ann Intern Med 123(1):18–26

    CAS  Article  Google Scholar 

  19. Weclawiak H, Kamar N, Mengelle C, Guitard J, Esposito L, Lavayssiere L, Cointault O, Ribes D, Rostaing L (2008) Cytomegalovirus prophylaxis with valganciclovir in cytomegalovirus-seropositive kidney-transplant patients. J Med Virol 80(7):1228–1232. https://doi.org/10.1002/jmv.21183

    CAS  Article  PubMed  Google Scholar 

  20. Fernandez-Ruiz M, Arias M, Campistol JM, Navarro D, Gomez-Huertas E, Gomez-Marquez G, Diaz JM, Hernandez D, Bernal-Blanco G, Cofan F, Jimeno L, Franco-Esteve A, Gonzalez E, Moreso FJ, Gomez-Alamillo C, Mendiluce A, Luna-Huerta E, Aguado JM (2015) Cytomegalovirus prevention strategies in seropositive kidney transplant recipients: an insight into current clinical practice. Transpl Int 28(9):1042–1054. https://doi.org/10.1111/tri.12586

    Article  PubMed  Google Scholar 

  21. Jung C, Engelmann E, Borner K, Offermann G (2001) Preemptive oral ganciclovir therapy versus prophylaxis to prevent symptomatic cytomegalovirus infection after kidney transplantation. Transplant Proc 33(7-8):3621–3623

    CAS  Article  Google Scholar 

  22. Caskurlu H, Karadag FY, Arslan F, Cag Y, Vahaboglu H (2019) Comparison of universal prophylaxis and preemptive approach for cytomegalovirus associated outcome measures in renal transplant patients: a meta-analysis of available data. Transpl Infect Dis 21(1):e13016. https://doi.org/10.1111/tid.13016

    Article  PubMed  Google Scholar 

  23. Hemmersbach-Miller M, Alexander BD, Sudan DL, Pieper C, Schmader KE (2019) Infections after kidney transplantation. Does age matter? Clin Transpl:e13516. https://doi.org/10.1111/ctr.13516

  24. Horvath MM, Rusincovitch SA, Brinson S, Shang HC, Evans S, Ferranti JM (2014) Modular design, application architecture, and usage of a self-service model for enterprise data delivery: the Duke Enterprise Data Unified Content Explorer (DEDUCE). J Biomed Inform 52:231–242. https://doi.org/10.1016/j.jbi.2014.07.006

    Article  PubMed  PubMed Central  Google Scholar 

  25. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG (2009) Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 42(2):377–381. https://doi.org/10.1016/j.jbi.2008.08.010

    Article  PubMed  Google Scholar 

  26. Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, Pikis A, Razonable RR, Miller V, Griffiths PD (2016) Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis 64(1):87–91. https://doi.org/10.1093/cid/ciw668

    Article  PubMed  PubMed Central  Google Scholar 

  27. CDC (2017) CDC/NHSN Surveillance Definitions for Specific Types of Infections. https://www.cdc.gov/nhsn/pdfs/pscmanual/17pscnosinfdef_current.pdf

  28. Razonable RR, Humar A (2013) Cytomegalovirus in solid organ transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 13(Suppl 4):93–106. https://doi.org/10.1111/ajt.12103

    CAS  Article  Google Scholar 

  29. Razonable RR, Humar A (2019) Cytomegalovirus in solid organ transplant recipients - Guidelines of the American Society of Transplantation Infectious Disease Community of Practice. Clinical transplantation:e13512. https://doi.org/10.1111/ctr.13512

  30. Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254

    CAS  Article  Google Scholar 

  31. Thomasini RL, Pereira DS, Pereira FSM, Mateo EC, Mota TN, Guimarães GG, Pereira LSM, Lima CX, Teixeira MM, Teixeira ALJ (2017) Aged-associated cytomegalovirus and Epstein-Barr virus reactivation and cytomegalovirus relationship with the frailty syndrome in older women. PLoS One 12(7):e0180841–e0180841. https://doi.org/10.1371/journal.pone.0180841

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Wang GC, Kao WH, Murakami P, Xue QL, Chiou RB, Detrick B, McDyer JF, Semba RD, Casolaro V, Walston JD, Fried LP (2010) Cytomegalovirus infection and the risk of mortality and frailty in older women: a prospective observational cohort study. Am J Epidemiol 171(10):1144–1152. https://doi.org/10.1093/aje/kwq062

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hayden RT, Yan X, Wick MT, Rodriguez AB, Xiong X, Ginocchio CC, Mitchell MJ, Caliendo AM (2012) Factors contributing to variability of quantitative viral PCR results in proficiency testing samples: a multivariate analysis. J Clin Microbiol 50(2):337–345. https://doi.org/10.1128/jcm.01287-11

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Lachance P, Chen J, Featherstone R, Sligl WI (2017) Association between cytomegalovirus reactivation and clinical outcomes in immunocompetent critically ill patients: a systematic review and meta-analysis. Open Forum Infect Dis 4(2):ofx029. https://doi.org/10.1093/ofid/ofx029

    Article  PubMed  PubMed Central  Google Scholar 

  35. Montoya JG, Giraldo LF, Efron B, Stinson EB, Gamberg P, Hunt S, Giannetti N, Miller J, Remington JS (2001) Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center. Clin Infect Dis 33(5):629–640. https://doi.org/10.1086/322733

    CAS  Article  PubMed  Google Scholar 

  36. Limaye AP, Bakthavatsalam R, Kim HW, Randolph SE, Halldorson JB, Healey PJ, Kuhr CS, Levy AE, Perkins JD, Reyes JD, Boeckh M (2006) Impact of cytomegalovirus in organ transplant recipients in the era of antiviral prophylaxis. Transplantation 81(12):1645–1652. https://doi.org/10.1097/01.tp.0000226071.12562.1a

    Article  PubMed  Google Scholar 

  37. McGillicuddy JW, Weimert NA, Taber DJ, Turner A, Mitchell LA, Wray DW, Egidi MF, Kuppachi S, Hughes MG, Baliga PK, Chavin KD (2010) Can preemptive cytomegalovirus monitoring be as effective as universal prophylaxis when implemented as the standard of care in patients at moderate risk? Transplantation 89(10):1218–1223. https://doi.org/10.1097/TP.0b013e3181d54ba6

    Article  PubMed  Google Scholar 

  38. Werzowa J, Schwaiger B, Hecking M, Strassl R, Schmaldienst S, Bohmig GA, Genser B, Saemann MD (2015) Prophylactic CMV therapy does not improve three-yr patient and graft survival compared to preemptive therapy. Clin Transpl 29(12):1230–1238. https://doi.org/10.1111/ctr.12657

    CAS  Article  Google Scholar 

  39. Brum S, Nolasco F, Sousa J, Ferreira A, Possante M, Pinto JR, Barroso E, Santos JR (2008) Leukopenia in kidney transplant patients with the association of valganciclovir and mycophenolate mofetil. Transplant Proc 40(3):752–754. https://doi.org/10.1016/j.transproceed.2008.02.048

    CAS  Article  PubMed  Google Scholar 

  40. Hwang SD, Lee JH, Lee SW, Kim JK, Kim MJ, Song JH (2018) Effect of low-dose vs standard-dose valganciclovir in the prevention of cytomegalovirus disease in kidney transplantation recipients: a systemic review and meta-analysis. Transplant Proc 50(8):2473–2478. https://doi.org/10.1016/j.transproceed.2018.01.023

    CAS  Article  PubMed  Google Scholar 

  41. Yang Y, Guerra CM, Sumrani N (2018) Effect of age on leukopenia following renal transplantation at a single center. Prog Transplant (Aliso Viejo, Calif):1526924818817017. https://doi.org/10.1177/1526924818817017

  42. Kumar D, Mian M, Singer L, Humar A (2017) An interventional study using cell-mediated immunity to personalize therapy for cytomegalovirus infection after transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 17(9):2468–2473. https://doi.org/10.1111/ajt.14347

    CAS  Article  Google Scholar 

  43. Lisboa LF, Kumar D, Wilson LE, Humar A (2012) Clinical utility of cytomegalovirus cell-mediated immunity in transplant recipients with cytomegalovirus viremia. Transplantation 93(2):195–200. https://doi.org/10.1097/TP.0b013e31823c1cd4

    Article  PubMed  Google Scholar 

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Funding

Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health under award number 5T32AI100851 (MHM, BDA) and National Institute on Aging (NIA) of the National Institutes of Health, Duke Pepper Older Americans Independence Center P30AG028716 (KES). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This research was also supported by an internal grant from the Duke Transplant Center (MHM).

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Affiliations

  1. Division of Infectious Diseases, Duke University Medical Center, Durham, NC, USA

    Marion Hemmersbach-Miller & Barbara D. Alexander

  2. Duke Clinical Research Institute, Durham, NC, USA

    Marion Hemmersbach-Miller

  3. Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA

    Carl F. Pieper

  4. Division of Geriatrics, Duke University Medical Center, Durham, NC, USA

    Kenneth E. Schmader

  5. GRECC, Durham VA, Durham, NC, USA

    Kenneth E. Schmader

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  1. Marion Hemmersbach-Miller
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  2. Barbara D. Alexander
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  4. Kenneth E. Schmader
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Correspondence to Marion Hemmersbach-Miller.

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The study was approved by the Duke University Health System Institutional Review Board for Clinical Investigation (Pro00076804). A waiver for informed consent was granted.

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Hemmersbach-Miller, M., Alexander, B.D., Pieper, C.F. et al. Age matters: older age as a risk factor for CMV reactivation in the CMV serostatus–positive kidney transplant recipient. Eur J Clin Microbiol Infect Dis 39, 455–463 (2020). https://doi.org/10.1007/s10096-019-03744-3

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  • DOI: https://doi.org/10.1007/s10096-019-03744-3

Keywords

  • Older adults
  • Cytomegalovirus
  • Kidney transplantation
  • Infection