Risk factors, survival, and impact of prophylaxis length in cytomegalovirus-seropositive lung transplant recipients: A prospective, observational, multicenter study
Victor Monforte
Respiratory Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Ciber Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Search for more papers by this authorHelena Sintes
Respiratory Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Ciber Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Search for more papers by this authorCristina López-Gallo
Respiratory Department, Hospital Puerta de Hierro, Madrid, Spain
Search for more papers by this authorMaria Delgado
Thoracic Surgery Department, Complexo Hospitalario Universitario A Coruña, A Coruña, Spain
Search for more papers by this authorFrancisco Santos
Respiratory Department, Hospital Reina Sofía, Córdoba, Spain
Search for more papers by this authorFelipe Zurbano
Respiratory Department, Hospital Marqués de Valdecilla, Santander, Spain
Search for more papers by this authorAmparo Solé
Respiratory Department, Hospital La Fe, Valencia, Spain
Search for more papers by this authorJoan Gavaldá
Infectious Disease Department, Hospital Universitari Vall d'Hebrón, Barcelona, Spain
Search for more papers by this authorJose Maria Borro
Thoracic Surgery Department, Complexo Hospitalario Universitario A Coruña, A Coruña, Spain
Search for more papers by this authorJavier Redel-Montero
Respiratory Department, Hospital Reina Sofía, Córdoba, Spain
Search for more papers by this authorJose Manuel Cifrian
Respiratory Department, Hospital Marqués de Valdecilla, Santander, Spain
Search for more papers by this authorAmparo Pastor
Respiratory Department, Hospital La Fe, Valencia, Spain
Search for more papers by this authorCorresponding Author
Antonio Román
Respiratory Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Ciber Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Correspondence
Antonio Román, Respiratory Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Email: [email protected]
Search for more papers by this authorPiedad Ussetti
Ciber Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Respiratory Department, Hospital Puerta de Hierro, Madrid, Spain
Search for more papers by this authorVictor Monforte
Respiratory Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Ciber Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Search for more papers by this authorHelena Sintes
Respiratory Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Ciber Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Search for more papers by this authorCristina López-Gallo
Respiratory Department, Hospital Puerta de Hierro, Madrid, Spain
Search for more papers by this authorMaria Delgado
Thoracic Surgery Department, Complexo Hospitalario Universitario A Coruña, A Coruña, Spain
Search for more papers by this authorFrancisco Santos
Respiratory Department, Hospital Reina Sofía, Córdoba, Spain
Search for more papers by this authorFelipe Zurbano
Respiratory Department, Hospital Marqués de Valdecilla, Santander, Spain
Search for more papers by this authorAmparo Solé
Respiratory Department, Hospital La Fe, Valencia, Spain
Search for more papers by this authorJoan Gavaldá
Infectious Disease Department, Hospital Universitari Vall d'Hebrón, Barcelona, Spain
Search for more papers by this authorJose Maria Borro
Thoracic Surgery Department, Complexo Hospitalario Universitario A Coruña, A Coruña, Spain
Search for more papers by this authorJavier Redel-Montero
Respiratory Department, Hospital Reina Sofía, Córdoba, Spain
Search for more papers by this authorJose Manuel Cifrian
Respiratory Department, Hospital Marqués de Valdecilla, Santander, Spain
Search for more papers by this authorAmparo Pastor
Respiratory Department, Hospital La Fe, Valencia, Spain
Search for more papers by this authorCorresponding Author
Antonio Román
Respiratory Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Ciber Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Correspondence
Antonio Román, Respiratory Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Email: [email protected]
Search for more papers by this authorPiedad Ussetti
Ciber Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Respiratory Department, Hospital Puerta de Hierro, Madrid, Spain
Search for more papers by this authorFunding information
This study was supported by Roche Pharma Spain.
Abstract
Background
The optimal length of cytomegalovirus (CMV) prophylaxis in lung transplantation according to CMV serostatus is not well established.
Methods
We have performed a prospective, observational, multicenter study to determine the incidence of CMV infection and disease in 92 CMV-seropositive lung transplant recipients (LTR), their related outcomes and risk factors, and the impact of prophylaxis length.
Results
At 18 months post transplantation, 37 patients (40%) developed CMV infection (23 [25%]) or disease (14 [15.2%]). Overall mortality was higher in patients with CMV disease (64.3% vs 10.2%; P<.001), but only one patient died from CMV disease. In the multivariate analysis, CMV disease was an independent death risk factor (odds ratio [OR] 18.214, 95% confidence interval [CI] 4.120-80.527; P<.001). CMV disease incidence was higher in patients with 90-day prophylaxis than in those with 180-day prophylaxis (31.3% vs 11.8%; P=.049). Prophylaxis length was an independent risk factor for CMV disease (OR 4.974, 95% CI 1.231-20.094; P=.024). Sixteen patients withdrew from prophylaxis because of adverse events.
Conclusion
CMV infection and disease in CMV-seropositive LTR remain frequent despite current prophylaxis. CMV disease increases mortality, whereas 180-day prophylaxis reduces the incidence of CMV disease.
References
- 1Balthesen M, Messerle M, Reddehase MJ. Lungs are a major organ site of cytomegalovirus latency and recurrence. J Virol. 1993; 67: 5360-5366.
- 2de la Torre-Cisneros J, Farinas MC, Caston JJ, et al. GESITRA-SEIMC/REIPI recommendations for the management of cytomegalovirus infection in solid-organ transplant patients. Enferm Infecc Microbiol Clin. 2011; 29: 735-758.
- 3Patel R, Paya CV. Infections in solid-organ transplant recipients. Clin Microbiol Rev. 1997; 10: 86-124.
- 4Cope AV, Sabin C, Burroughs A, Rolles K, Griffiths PD, Emery VC. Interrelationships among quantity of human cytomegalovirus (HCMV) DNA in blood, donor-recipient serostatus, and administration of methylprednisolone as risk factors for HCMV disease following liver transplantation. J Infect Dis. 1997; 176: 1484-1490.
- 5Humar A, Snydman D. AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009; 9(Suppl 4): S78-S86.
- 6Axelrod D, Leventhal JR, Gallon LG, Parker MA, Kaufman DB. Reduction of CMV disease with steroid-free immunosuppresssion in simultaneous pancreas-kidney transplant recipients. Am J Transplant. 2005; 5: 1423-1429.
- 7Hibberd PL, Tolkoff-Rubin NE, Cosimi AB, et al. Symptomatic cytomegalovirus disease in the cytomegalovirus antibody seropositive renal transplant recipient treated with OKT3. Transplantation. 1992; 53: 68-72.
- 8Turgeon N, Fishman JA, Basgoz N, et al. Effect of oral acyclovir or ganciclovir therapy after preemptive intravenous ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus seropositive renal and liver transplant recipients receiving antilymphocyte antibody therapy. Transplantation. 1998; 66: 1780-1786.
- 9Fishman JA, Emery V, Freeman R, et al. Cytomegalovirus in transplantation—Challenging the status quo. Clin Transplant. 2007; 21: 149-158.
- 10Sharples LD, Tamm M, McNeil K, Higenbottam TW, Stewart S, Wallwork J. Development of bronchiolitis obliterans syndrome in recipients of heart-lung transplantation–early risk factors. Transplantation. 1996; 61: 560-566.
- 11Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant. 1996; 15: 1-15.
- 12Verleden GM. Chronic allograft rejection (obliterative bronchiolitis). Semin Respir Crit Care Med. 2001; 22: 551-558.
- 13Cooper JD, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 1993; 12: 713-716.
- 14Hayes D Jr. A review of bronchiolitis obliterans syndrome and therapeutic strategies. J Cardiothorac Surg. 2011; 6: 92.
- 15de Perrot M, Chaparro C, McRae K, et al. Twenty-year experience of lung transplantation at a single center: Influence of recipient diagnosis on long-term survival. J Thorac Cardiovasc Surg. 2004; 127: 1493-1501.
- 16Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Twenty-seventh official adult lung and heart-lung transplant report–2010. J Heart Lung Transplant. 2010; 29: 1104-1118.
- 17Snyder LD, Wang Z, Chen DF, et al. Implications for human leukocyte antigen antibodies after lung transplantation: A 10 year experience in 441 patients. Chest. 2013; 144: 226-233.
- 18Paraskeva M, Bailey M, Levvey BJ, et al. Cytomegalovirus replication within the lung allograft is associated with bronchiolitis obliterans syndrome. Am J Transplant. 2011; 11: 2190-2196.
- 19Humbert M, Devergne O, Cerrina J, et al. Activation of macrophages and cytotoxic cells during cytomegalovirus pneumonia complicating lung transplantations. Am Rev Respir Dis. 1992; 145: 1178-1184.
- 20Humbert M, Emilie D. [Immunopathology of cytomegalovirus pneumonia and allograft rejection in lung transplantation. Group of Pulmonary Transplantation of the University Paris-Sud]. Rev Mal Respir. 1994; 11: 559-564.
- 21Speich R, Thurnheer R, Gaspert A, Weder W, Boehler A. Efficacy and cost effectiveness of oral ganciclovir in the prevention of cytomegalovirus disease after lung transplantation. Transplantation. 1999; 67: 315-320.
- 22Chmiel C, Speich R, Hofer M, et al. Ganciclovir/valganciclovir prophylaxis decreases cytomegalovirus-related events and bronchiolitis obliterans syndrome after lung transplantation. Clin Infect Dis. 2008; 46: 831-839.
- 23Ruttmann E, Geltner C, Bucher B, et al. Combined CMV prophylaxis improves outcome and reduces the risk for bronchiolitis obliterans syndrome (BOS) after lung transplantation. Transplantation. 2006; 81: 1415-1420.
- 24Hodson EM, Jones CA, Webster AC, et al. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: A systematic review of randomised controlled trials. Lancet. 2005; 365: 2105-2115.
- 25Monforte V, Lopez C, Santos F, et al. A multicenter study of valganciclovir prophylaxis up to day 120 in CMV-seropositive lung transplant recipients. Am J Transplant. 2009; 9: 1134-1141.
- 26Hammond SP, Martin ST, Roberts K, et al. Cytomegalovirus disease in lung transplantation: Impact of recipient seropositivity and duration of antiviral prophylaxis. Transpl Infect Dis. 2013; 15: 163-170.
- 27Finlen Copeland CA, Davis WA, Snyder LD, et al. Long-term efficacy and safety of 12 months of valganciclovir prophylaxis compared with 3 months after lung transplantation: A single-center, long-term follow-up analysis from a randomized, controlled cytomegalovirus prevention trial. J Heart Lung Transplant. 2011; 30: 990-996.
- 28Meyer-Koenig U, Weidmann M, Kirste G, Hufert FT. Cytomegalovirus infection in organ-transplant recipients: Diagnostic value of pp65 antigen test, qualitative polymerase chain reaction (PCR) and quantitative Taqman PCR. Transplantation. 2004; 77: 1692-1698.
- 29Mwintshi K, Brennan DC. Prevention and management of cytomegalovirus infection in solid-organ transplantation. Expert Rev Anti Infect Ther. 2007; 5: 295-304.
- 30Kotton CN, Kumar D, Caliendo AM, et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010; 89: 779-795.
- 31Borro JM. [Lung transplants in Spain: An update]. Arch Bronconeumol. 2005; 41: 457-467.
- 32Hodson EM, Craig JC, Strippoli GF, Webster AC. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev. 2008; (2): CD003774.
- 33Pescovitz MD, Rabkin J, Merion RM, et al. Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents Chemother. 2000; 44: 2811-2815.
- 34Zuk DM, Humar A, Weinkauf JG, Lien DC, Nador RG, Kumar D. An international survey of cytomegalovirus management practices in lung transplantation. Transplantation. 2010; 90: 672-676.
- 35Razonable RR, Humar A, AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant. 2013; 13(Suppl 4): 93-106.
- 36Schoeppler KE, Lyu DM, Grazia TJ, Crossno JT Jr, Vandervest KM, Zamora MR. Late-onset cytomegalovirus (CMV) in lung transplant recipients: Can CMV serostatus guide the duration of prophylaxis? Am J Transplant. 2013; 13: 376-382.
- 37Jaksch P, Zweytick B, Kerschner H, et al. Cytomegalovirus prevention in high-risk lung transplant recipients: Comparison of 3- vs 12-month valganciclovir therapy. J Heart Lung Transplant. 2009; 28: 670-675.
- 38Mitsani D, Nguyen MH, Kwak EJ, et al. Cytomegalovirus disease among donor-positive/recipient-negative lung transplant recipients in the era of valganciclovir prophylaxis. J Heart Lung Transplant. 2010; 29: 1014-1020.
- 39Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis. 2002; 34: 1094-1097.
- 40Zamora MR, Nicolls MR, Hodges TN, et al. Following universal prophylaxis with intravenous ganciclovir and cytomegalovirus immune globulin, valganciclovir is safe and effective for prevention of CMV infection following lung transplantation. Am J Transplant. 2004; 4: 1635-1642.
- 41Palmer SM, Limaye AP, Banks M, et al. Extended valganciclovir prophylaxis to prevent cytomegalovirus after lung transplantation: A randomized, controlled trial. Ann Intern Med. 2010; 152: 761-769.
- 42Humar A, Kumar D, Preiksaitis J, et al. A trial of valganciclovir prophylaxis for cytomegalovirus prevention in lung transplant recipients. Am J Transplant. 2005; 5: 1462-1468.
- 43Valentine VG, Weill D, Gupta MR, et al. Ganciclovir for cytomegalovirus: A call for indefinite prophylaxis in lung transplantation. J Heart Lung Transplant. 2008; 27: 875-881.
- 44Wiita AP, Roubinian N, Khan Y, et al. Cytomegalovirus disease and infection in lung transplant recipients in the setting of planned indefinite valganciclovir prophylaxis. Transpl Infect Dis. 2012; 14: 248-258.
- 45Manuel O, Husain S, Kumar D, et al. Assessment of cytomegalovirus-specific cell-mediated immunity for the prediction of cytomegalovirus disease in high-risk solid-organ transplant recipients: A multicenter cohort study. Clin Infect Dis. 2013; 56: 817-824.
- 46Weseslindtner L, Kerschner H, Steinacher D, et al. Association of human cytomegalovirus DNAaemia and specific granzyme B responses in lung transplant recipients. Clin Exp Immunol. 2013; 173: 438-443.
- 47Doesch AO, Repp J, Hofmann N, et al. Effects of oral valganciclovir prophylaxis for cytomegalovirus infection in heart transplant patients. Drug Des Devel Ther. 2012; 6: 289-295.
- 48Kiser TH, Fish DN, Zamora MR. Evaluation of valganciclovir pharmacokinetics in lung transplant recipients. J Heart Lung Transplant. 2012; 31: 159-166.
- 49Trevillyan J, Angus P, Shelton E, et al. Electronic estimations of renal function are inaccurate in solid-organ transplant recipients and can result in significant underdosing of prophylactic valganciclovir. Antimicrob Agents Chemother. 2013; 57: 4058-4060.
- 50Imamura T, Shiga T, Kinugawa K, et al. Successful conversion to everolimus after cytomegalovirus infection in a heart transplant recipient. Int Heart J. 2012; 53: 199-201.
- 51Sebbag L, Boucher P, Davelu P, et al. Thiopurine S-methyltransferase gene polymorphism is predictive of azathioprine-induced myelosuppression in heart transplant recipients. Transplantation. 2000; 69: 1524-1527.
- 52Reindl-Schwaighofer R, Oberbauer R. Blood disorders after kidney transplantation. Transplant Rev (Orlando). 2014; 28: 63-75.
- 53Hartmann EL, Gatesman M, Roskopf-Somerville J, Stratta R, Farney A, Sundberg A. Management of leukopenia in kidney and pancreas transplant recipients. Clin Transplant. 2008; 22: 822-828.
- 54Vrtovec B, Haddad F, Pham M, et al. Granulocyte colony-stimulating factor therapy is associated with a reduced incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients. Transplant Proc. 2013; 45: 2406-2409.
- 55San Juan R, Aguado JM, Lumbreras C, et al. Impact of current transplantation management on the development of cytomegalovirus disease after renal transplantation. Clin Infect Dis. 2008; 47: 875-882.
- 56McGee J, Mave V, Yau CL, et al. Cytomegalovirus disease in African-American kidney transplant patients. Transpl Infect Dis. 2012; 14: 604-610.
- 57Oh CK, Sanfey HA, Pelletier SJ, Sawyer RG, McCullough CS, Pruett TL. Implication of advanced donor age on the outcome of liver transplantation. Clin Transplant. 2000; 14: 386-390.
- 58Furui Y, Satake M, Hoshi Y, Uchida S, Suzuki K, Tadokoro K. Cytomegalovirus (CMV) seroprevalence in Japanese blood donors and high detection frequency of CMV DNA in elderly donors. Transfusion. 2013; 53: 2190-2197.
- 59Grundy JE, Lui SF, Super M, et al. Symptomatic cytomegalovirus infection in seropositive kidney recipients: Reinfection with donor virus rather than reactivation of recipient virus. Lancet. 1988; 2: 132-135.
- 60Singh N, Arnow PM, Bonham A, et al. Invasive aspergillosis in liver transplant recipients in the 1990s. Transplantation. 1997; 64: 716-720.
- 61Snydman DR, Limaye AP, Potena L, Zamora MR. Update and review: State-of-the-art management of cytomegalovirus infection and disease following thoracic organ transplantation. Transplant Proc. 2011; 43: S1-S17.
- 62Husain S, Singh N. Bronchiolitis obliterans and lung transplantation: Evidence for an infectious etiology. Semin Respir Infect. 2002; 17: 310-314.
- 63Snyder LD, Finlen-Copeland CA, Turbyfill WJ, Howell D, Willner DA, Palmer SM. Cytomegalovirus pneumonitis is a risk for bronchiolitis obliterans syndrome in lung transplantation. Am J Respir Crit Care Med. 2010; 181: 1391-1396.
